MX2008000512A - Piperidine derivatives useful in the diagnostic and therapeutic treatment of diseases depending on renin activity. - Google Patents

Piperidine derivatives useful in the diagnostic and therapeutic treatment of diseases depending on renin activity.

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Publication number
MX2008000512A
MX2008000512A MX2008000512A MX2008000512A MX2008000512A MX 2008000512 A MX2008000512 A MX 2008000512A MX 2008000512 A MX2008000512 A MX 2008000512A MX 2008000512 A MX2008000512 A MX 2008000512A MX 2008000512 A MX2008000512 A MX 2008000512A
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carbon atoms
alkyl
amino
phenyl
unsubstituted
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MX2008000512A
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Spanish (es)
Inventor
Takanori Kanazawa
Keiichi Masuya
Fumiaki Yokokawa
Kazuhide Konishi
Claus Ehrhardt
Werner Breitenstein
Nils Ostermann
Juergen Klaus Maibaum
Edgar Jacoby
Philipp Grosche
Juerg Zimmermann
Andreas Marzinzik
Shimpei Kawakami
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Novartis Ag
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Publication of MX2008000512A publication Critical patent/MX2008000512A/en

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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Hydrogenated Pyridines (AREA)

Abstract

The invention relates to 3,5-substituted piperidine compounds, these compounds for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (= disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations comprising a 3,5-substituted piperidine compound, and/or a method of treatment comprising administering a 3,5-substituted piperidine compound, a method for the manufacture of a 3, 5-substituted piperidine compound, and novel intermediates and partial steps for its synthesis. The preferred compounds (which can also be present as salts) have the formula I wherein R1 , R2, T, R3 and R4 are as defined in the specification.

Description

PIPERIDINE DERIVATIVES USEFUL IN THE DIAGNOSIS AND THE THERAPEUTIC TREATMENT OF DISEASES DEPENDENTS OF THE ACTIVITY OF LA RENIÑA The invention relates to 3,5-substituted piperidine compounds, to these compounds for use in the diagnosis and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (= disorder) that depends on the activity of renin; to the use of a compound of this class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on the activity of renin; to the use of a compound of this class in the treatment of a disease that depends on the activity of renin; to pharmaceutical formulations comprising a 3,5-substituted piperidine compound, and / or to a method of treatment, which comprises administering a 3,5-substituted piperidine compound, to a method for the manufacture of a piperidine 3 compound, 5-substituted, and novel intermediaries and partial steps for its synthesis. The present invention relates to a compound of the formula | where: R1 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl; R2 is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; R3 is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted alkyl, R4 is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; and T is methylene (CH2) or carbonyl (C (= 0)); or a salt (preferably pharmaceutically acceptable) thereof. The compounds of the present invention exhibit an inhibitory activity on the natural enzyme renin. Accordingly, the compounds of the formula I can be used for the treatment (including this term also the prophylaxis) of one or more disorders or diseases, in particular, selected from the diseases given in detail below, especially as far as these diseases can be modulated (more especially beneficially influenced) by the inhibition of renin.
The definitions of the different terms used to describe the compounds of the present invention, as well as their use and synthesis, starting materials and intermediates and the like are listed below. These definitions, by the replacement of one, more than one, or all the general expressions or symbols employed in the present disclosure and consequently, by providing the preferred embodiments of the invention, preferably apply to the terms as they are used throughout. all descriptive memory, unless otherwise limited in specific instances, either individually or as part of a larger group. The term "lower" or "Ci-C -" defines a fraction with up to and including maximum 7, especially up to and including maximum 4, carbon atoms, this fraction being branched chain (one or more times) or straight chain , and being linked by means of a terminal or non-terminal carbon atom. Lower alkyl or from 1 to 7 carbon atoms, for example, is normal pentyl, normal hexyl, or normal heptyl, or preferably alkyl of 1 to 4 carbon atoms, especially as methyl, ethyl, normal propyl, secondary propyl, normal butyl, isobutyl, secondary butyl or tertiary butyl. Halo or halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine. If not otherwise explicitly or implicitly mentioned, halogen may also represent more than one halogen substituent in such moieties as alkyl, alkanoyl, and the like (eg, in trifluoromethyl, trifluoroacetyl). Unsubstituted or substituted alkyl is preferably alkyl of 1 to 20 carbon atoms, more preferably alkyl of 1 to 7 carbon atoms, which is straight or branched chain (one, or where appropriate, more times), which is unsubstituted or substituted by one or more, for example, up to three fractions selected from unsubstituted or substituted heterocyclyl as described below, especially pyrrolyl, furanyl, thienyl (= thiophenyl), thiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxetidinyl, - (C 1-7 -alkyl) -oxetidinyl, pyridyl, pyrimidinyl, morpholino, thiomorpholino, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydro-furanonyl, tetrahydro-pyranyl, 1 H-indazanyl, benzo-furanyl, benzo-thiophenyl, ( more preferably) isoquinolinyl, quinolinyl or especially indolyl, each of which is unsubstituted or substituted as described below for unsubstituted or substituted heterocyclyl, for example, from one to three is substituents independently selected from hydroxyl, halogen, such as chloro, alkyl of 1 to 7 carbon atoms, such as methyl, cyano, and alkanoyl of 1 to 7 carbon atoms, such as acetyl; starting from unsubstituted or substituted cycloalkyl as described below, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or substituted as described below for unsubstituted or substituted cycloalkyl, especially for up to four fractions of alkyl of 1 to 7 carbon atoms; from unsubstituted or substituted aryl as described further below, especially unsubstituted or substituted phenyl, naphthyl, indenyl or indanyl; and from the group consisting of alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, as trifluoro-methoxy, hydroxy-alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenyl- or naphthyl-oxy, phenyl- or naphthy-alkyloxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, (alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms (with hydroxyl not in position 1), alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-car-bonyloxy, benzoyl- or naphthoyloxy, thioalkyl of 1 to 7 carbon atoms , halo-thioalkyl of 1 to 7 carbon atoms, such as tri-fluoro-thiomethyl, hydroxy-thioalkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-thioalkyl or from 1 to 7 carbon atoms, thiophenyl or thionaphthyl, phenyl- or naphthyl-thioalkyl of 1 to 7 carbon atoms, nitro, amino, mono- or di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms (with hydroxyl not in position 1) and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -amino, alkanoyl of 1 to 7 carbon atoms-amino, benzoyl- or naphthoylamino, alkyl of 1 to 7 carbon atoms-sulfonyl-amino, phenyl- Naphthylsulfonyl-amino, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms carbon-sulfonyl-amino, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-carbonyl-amino, carboxyl, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, phenyl- or naphthyloxycarbonyl, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms-carbonyl, carbamoyl, N- mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-carbonyl, N -mono- or N, N-di- (naphthyl- or phenyl-alkyl of 1 to 7 carbon atoms), hydroxy-alkyl of 2 to 7 carbon atoms (with the hydroxyl not in position 1) and / or alkoxy from 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -amino-carbonyl, cyano, sulfenyl (-S-OH), sulfonyl (-S (= 0) -OH), alkyl of 1 to 7 carbon atoms-sulfinyl (alkyl of 1 to 7 carbon atoms-S (= 0) -), phenyl- or naphthyl sulfyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms -sulphinyl, sulfonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, phenyl- or naphthyl-sulfonyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfonyl, sulphamoyl, N-mono- or N, N -di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl, N-mono-, N'-mono-, N, N-di- or N, N, N'- tri- (C 1-7 -alkyl, hydroxy-C 2-7 -alkyl (with hydroxy not in position 1), C 1-7 -alkoxy-C 1-7 -alkyl , phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms) -arino-carbonyl-amino or -amino-carbonyloxy and N-mono-, N'-mono -, N, N-di- or N, N, N'-tri- (alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms (with the hydroxyl not in position 1), alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl -alkyl of 1 to 7 carbon atoms) -amino-sulfonyl-amino; wherein any phenyl, naphthyl, indenyl, indanyl, pyridyl or indolinyl mentioned as a substituent or as part of a substituted alkyl substituent (mentioned in the preceding paragraph) is unsubstituted or substituted by one or more, preferably up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, alkenyl of 1 to 7 carbon atoms, alkynyl of 1 to 7 carbon atoms carbon, haloalkyl of 1 to 7 carbon atoms, such as trifluoromethyl, halogen, especially fluorine, chlorine, bromine or iodine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy from 1 to 7 carbon atoms, phenyloxyl, naphthyloxy, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkanoyloxy of 1 to 7 carbon atoms, amino , mono- or di- (alkyl of 1 at 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms and / or phenyl- or naphthyl-alkanoyl of one to 7 carbon atoms) -amino, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl, phenoxycarbonyl, naphthyloxy-carbonyl, phenyl-alkyloxy of 1 to 7 carbon atoms-carbonyl, naphthyl-alkoxy of 1 to 7 atoms carbon- carbonyl, carbamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) carbon) -aminocarbonyl, cyano, sulfonyl, sulfamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl and nitro, or preferably, where preferred substituents are mentioned, by one or more of these mentioned substituents. Especially unsubstituted or substituted alkyl (especially as R2 or as part of the acrylic R4) is phenyl-methyl, 2-cyclohexyl-2-phenyl-ethyl, 2,2-diphenyl-ethyl, 2,2-diphenyl-n -butyl, 2,3-diphenyl-n-propyl, naphthyl-methyl, 2-phenyl-2-pyridyl-ethyl, indolyl-methyl, 2-alkoxy of 1 to 7 carbon atoms-carbonyl-2,2-diphenyl- ethyl, 4-methyl-2-phenyl-n-pentyl or 5-alkoxy of 1 to 7 carbon atoms-2-diphenyl-methyl-pentyl, wherein any phenyl, naphthyl, pyridyl or indolyl mentioned as substituted alkyl substituent is unsubstituted or substituted by one or more, especially up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms carbon-alkyl of 1 to 7 carbon atoms,? -hydroxy-alkoxy of 2 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, halo-alkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 á carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenyl, halogen, especially chlorine or bromine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenoxy, halo-alkoxy of 1 to 7 carbon atoms, amino, alkanoyl of 1 to 7 carbon atoms-amino, alkane of 1 to 7 atoms carbon-sulfonyl and cyano (wherein, preferably any fraction mentioned above, comprises an O, halogen, or S by which it is bonded or not bound to a nitrogen ring). Unsubstituted or substituted alkenyl is preferably alkenyl of 2 to 20 carbon atoms, more preferably alkenyl of 2 to 7 carbon atoms with one or, if possible, more double bonds, which are straight or branched chain (or, where be appropriate, more times), which is unsubstituted or substituted by one or more, for example, up to three fractions selected from those mentioned as substituents for substituted alkyl and from unsubstituted or substituted aryl, each preferably as described above or more ahead. Substituents with an active hydrogen (eg, hydroxyl or amino) are preferably present in the form of tautomers in equilibrium if they are directly linked to a carbon atom with a double bond; in these preferred positions the substituents with active hydrogen are avoided. Unsubstituted or substituted alkynyl is preferably alkynyl of 2 to 10 carbon atoms, more preferably alkynyl of 2 to 7 carbon atoms with one or, if possible, more triple bonds, which are straight or branched chain (one or, in where appropriate, more times), which is unsubstituted or substituted by one or more, for example, up to three fractions selected from those mentioned as substituents for substituted alkyl and from unsubstituted or substituted aryl, each preferably as described above or later . Substituents with an active hydrogen (eg, hydroxyl or amino) are preferably present in the form of tautomers at equilibrium if they are directly linked to a carbon atom with a triple bond; in these preferred positions the substituents with active hydrogen are avoided. Unsubstituted or substituted aryl is preferably a mono- or bi-cyclic aryl having 6 to 22 carbon atoms, especially phenyl, indenyl, indanyl or naphthyl, and is unsubstituted or substituted by one or more, especially one to three, fractions , preferably independently selected from the group consisting of a substituent of the formula - (alkylene of 0 to 7 carbon atoms) - (X) r- (alkylene of 1 to 7 carbon atoms) - (Y) s- (C 7 -C 7 alkylene) -H (especially in substituted aryl, or aryl-alkyl substituted as R 2) wherein C 0 -C 0 alkylene means that a bond is present in place of bound alkylene, alkylene in each case may be straight or branched chain, and is unsubstituted, or (with a lower preference) substituted for example, by one or more fractions as defined for substituted alkyl, especially by halogen, especially fluorine, hydroxyl, alkoxy. at 7 carbon atoms, phenyloxy, naphthyloxy, C 1 -C 7 -alkanoyloxy, benzoyloxy, naphthyloxy, amino, mono- or di- (C 1-7 -alkyl, C 1-7 -alkanoyl, phenyl-C 1-7 -alkanoyl, naphthyl alkanoyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino, carboxyl, alkoxy of 1 to 7 atoms carbon-carbonyl or cyano, rys, each independently of the other, are 0 or 1, and each of X and Y, if they are present and independently of the others, is -O-, -NV-, -S-, -O-CO-, -CO-O-, -NV-CO-; -CO-NV-; -NV-S02-, -SO2-NV; -NV-CO-NV-, -NV-CO-O-, -O-CO-NV-, -NV-S02-NV-, wherein V is hydrogen or unsubstituted or substituted alkyl as defined above, especially alkyl from 1 to 7 carbon atoms, or is phenyl, naphthyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms or halo-alkyl of 1 to 7 carbon atoms; wherein the substituent of - (alkylene of 0 to 7 carbon atoms) - (X) r- (alkylene of 1 to 7 carbon atoms) - (Y) s- (alkylene of 0 to 7 carbon atoms) -H it is preferably alkyl of 1 to 7 carbon atoms, such as methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl or tertiary butyl, haloalkyl of 1 to 7 carbon atoms, such as trifluoromethyl , hydroxy-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, such as 3-methoxy-propyl or 2-methoxy-ethyl,? -hydroxy-alkoxy 2 to 7 carbon atoms - alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms - alkoxy of 1 to 7 carbon atoms - alkyl of 1 to 7 carbon atoms carbon, phenyloxy- or naphthyloxy-alkyl of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, amino-alkyl of 1 to 7 carbon atoms, such as aminomethyl, alkoxy from 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms, mono- or di- (alkyl of 1 to 7 carbon atoms, naphthyl-, phenyl, naphthyl- alkyl of 1 to 7 carbon atoms and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-O-CO-NH-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-sulfonyl-amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-NH-CO-NH-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-NH-S02-NH-alkyl of 1 to 7 carbon atoms, alkoxy from 1 to 7 carbon atoms, hydroxy-alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, such as trifluoromethoxyl, phenyl- or naphthyl-alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-amino-carbonyloxy, halotioalkyl of 1 to 7 carbon atoms, such as trifluorothiomethyl, phenyl- or naphthylthioalkyl of 1 to 7 carbon atoms, mono- or di- (alkyl of 1 to 7 carbon atoms-, naphthyl-alkyl of 1 to 7 carbon atoms) -, phenyl-alkyl of 1 to 7 carbon atoms- and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-) amino, alkanoyl of 1 to 7 carbon atoms-amino, alkyl of 1 to 7 carbon atoms-sulfonyl-amino, phenyl- or naphthyl-alkanoyl of 1 to 7 carbon atoms-amino, phenyl- or naphthyl-alkyl of 1 to 7 carbon-amino-carbonyl-amino, carboxy-alkyl atoms of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-carbonyl, hydroxy-alkoxy of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon-alkoxy atoms of 1 to 7 carbon atoms-carbonyl, amino-alkoxy of 1 to 7 carbon atoms-carbonyl, (N-) mono- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 at 7 carbon atoms-carbonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkoxy of 1 to 7 carbon atoms-carbonyl, N- mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) , naphthyl-alkyl of 1 to 7 carbon atoms and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, halo-alkyl of 1 to 7 carbon atoms carbon-sulfonyl, hydroxy-alkyl of 1 at 7 carbon atoms-sulfonyl, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-sulfonyl, amino-alkyl of 1 to 7 carbon atoms-sulfonyl, N-mono- or di- (alkyl) from 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms-sulfonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms-sulfonyl, N-alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-carbamoyl or N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-sulfonyl; from alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, phenyl, naphthyl, heterocyclyl, especially as is defined below for heterocyclyl, preferably selected from pyrrolyl, furanyl, thienyl, pyrimidine-2,4-dione-1-, -3- or -5-yl and tetrahydro-furanyl, [phenyl- or naphthyl- heterocyclyl or trihalo (especially trifluoro) -methoxy] -alkyl of 1 to 7 carbon atoms or -alkyloxy of 1 to 7 carbon atoms, wherein phenyl or naphthyl is preferably unsubstituted or substituted, preferably by alkoxy of 1 to 7 carbon and / or halogen atoms and wherein heterocyclyl is as defined below, preferably selected from pyrrolyl, furanyl, tetrahydro-furanyl, tetrahydro-pyranyl and thienyl; such as benzyl or naphthylmethyl, tetrahydro-furanyl- or tetrahydro-pyranyl-alkyl of 1 to 7 carbon atoms, benzoyl- or naphthoylamino-alkyl of 1 to 7 carbon atoms, (phenyl- or naphthyl- or heterocyclyl) -) - sulfonyl-amino-alkyl of 1 to 7 carbon atoms, wherein phenyl or naphthyl or heterocyclyl is unsubstituted or substituted, preferably by one or more, in particular one to three, alkyl fractions of 1 to 7 carbon atoms carbon, (phenyl or naphthyl or heterocyclyl) -alkyl of 1 to 7 carbon atoms-sulfonyl-amino-alkyl of 1 to 7 carbon atoms, halogen, hydroxyl, (heterocyclyl or phenyl or naphthyl) -oxyl, naphthyl-alkyloxy 1 to 7 carbon atoms, benzoyl or naphthoyl or heterocyclyl-carbonyl) -oxyl, (phenyl or naphthyl or heterocyclyl) -amino-carbonyloxy, thio- (phenyl or naphthyl or heterocyclyl), thio- (benzoyl or naphthoyl or heterocyclyl), nitro, amino, di - ((naphthyl or phenyl or heterocyclyl) -alkyl of 1 to 7 carbon atoms) -amino, (benzoyl or naphthoyl or hetero iclyl) -amino, (phenyl or naphthyl or heterocyclyl) -carbonyl of 1 to 7 carbon atoms-amino, (phenyl or naphthyl or heterocyclyl) -sulfonyl-amino, wherein phenyl or naphthyl is unsubstituted or is preferably substituted by one or more, in particular one to three alkyl fractions of 1 to 7 carbon atoms, (phenyl or naphthyl or heterocyclyl) ) -alkyl of 1 to 7 carbon atoms-sulfonyl-amino, (phenyl or naphthyl or heterocyclyl) -amino-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) of 1 to 7 carbon atoms-amino-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) -oxi-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) -alkyloxy from 1 to 7 carbon atoms-carbonyl-amino, carboxyl, alkyl of 1 to 7 carbon atoms, halo- alkyl of 1 to 7 carbon atoms-carbonyl, hydroxy-alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-carbonyl, amino-alkyl of 1 to 7 carbon atoms-carbonyl, (N- ) mono- or (N, N-) di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms-carbonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 at 7 carbon atoms - carbonyl, haloalkoxy of 1 to 7 carbon atoms - carbonyl, (phenyl or naphthyl or heterocyclyl (especially mono- or bi-cyclic)) - oxycarbonyl, (phenyl or naphthyl or heterocyclyl) -alkoxy of 1 to 7 carbon atoms-carbonyl, (N, N -) - di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms -carbonyl, carbamoyl, N-mono - or N, N-di- (naphthyl or phenyl or heterocyclyl) -amino-carbonyl, cyano, C 1 -C 7 alkylene which is unsubstituted or substituted by up to four C 1 to C 7 alkyl substituents to two adjacent atoms of ring of the aryl, sulfenyl, sulfinyl, alkyl of 1 to 7 carbon atoms-sulfinyl, (phenyl or naphthyl or heterocyclyl) -sulfinyl, wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially one to three, alkyl fractions of 1 to 7 carbon atoms, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfinyl, sulfonyl, (phenyl or naphthyl or heterocyclyl) -sulfonyl, wherein phenyl or naphthyl is unsubstituted or preferably substituted by one or more, especially one to three, alkyl fractions of 1 to 7 carbon atoms, (phenyl or naphthyl or heterocyclyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, sulfamoyl and N-mono - or N, N-di- (C 1-7 -alkyl, phenyl, naphthyl, heterocyclyl, phenyl-C 1-7 -alkyl, naphthyl-C 1-7 -alkyl and / or heterocyclyl) alkyl of 1 to 7 carbon atoms) -amino-sulfonyl; wherein any phenyl or naphthyl or heterocyclyl (which heterocyclyl is preferably as defined for heterocyclyl, more preferably is selected from pyrrolyl, furanyl, tetrahydro-furanyl, tetrahydro-pyranyl and thienyl) mentioned as a substituent of, or as part of, a substituted aryl substituent mentioned in one of the two preceding paragraphs is unsubstituted or substituted by one or more, preferably up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, alkenyl of 1 to 7 carbon atoms, alkynyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, such as trifluoromethyl, halogen, in particular fluorine, chlorine, bromine or iodine, hydroxyl, alkoxy of 1 to 7 carbon atoms, phenyloxyl, naphthyloxy, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkanoyloxy having 1 to 7 carbon atoms, amino, mono- or di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl- 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms and / or phenyl- or naphthyl-alkanoyl of 1 to 7 carbon atoms) -amino, carboxyl, alkoxy of 1 to 7 carbon atoms -carbonyl, phenoxy- carbonyl, naphthyloxycarbonyl, phenyl-alkyloxy of 1 to 7 carbon atoms-carbonyl, naphthyl-alkoxy of 1 to 7 carbon atoms, carbamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthylalkyl of 1 to 7 carbon atoms) -amino-carbonyl, cyano, sulfonyl, sulphamoyl, N-mono- or N, N -di- (al 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl and nitro, or preferably, wherein Preferred substituents are mentioned, by one or more of these mentioned substituents. Unsubstituted or substituted heterocyclic is preferably a mono- or bicyclic heterocyclic moiety with an unsaturated, partially saturated, or saturated ring system, preferably 3 to 22 (more preferably 3 to 14) ring atoms and with one or more, of one to four preference, heteroatoms independently selected from nitrogen (= N-, -NH- or -NH- substituted), oxygen and sulfur (-S-, S (= 0) - or S - (= 0) 2-) which is unsubstituted or substituted by one or more, for example, up to three, substituents preferably independently selected from the substituents mentioned above for aryl (wherein, preferably these substituents comprising an S, O, or halogen which is linked to heterocyclyl are not linked by a ring nitrogen atom), and from oxo (= 0) and thioxo (= S). Preferably, unsubstituted or substituted heterocyclyl is selected from the following fractions: X ÍA fX X SO X 'SOX OR SO X' SO. ca cai oi i ax p ox M. : H? 0 H ° io * o H o? H wherein, in each case, when an H linked to a ring atom is present by linking with the asterisk connecting the respective heterocyclyl moiety with the rest of the molecule, the H can be replaced with said link and, if they are present one or more additional H atoms bonded to a ring atom, may be replaced by one or more substituents as just described. Very preferred as unsubstituted or substituted heterocyclyl are tetrahydro-furanyl, tetrahydro-pyranyl, piperidinyl, pyridyl, thiophenyl, thiazolyl, pyrazolyl, indolyl, quinolinyl or 2H-1,4-benzoxazin-3 (4H) -onyl, each of which is unsubstituted or substituted by one or more, especially up to three substituents independently selected from the substituents mentioned for aryl previously substituted, especially by one or more, especially up to three, independently selected fractions from the group consisting of alkyl from 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenyl, halogen, especially chlorine or bromine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenoxy, halo- alkoxyl d and 1 to 7 carbon atoms, amino, alkanoyl of 1 to 7 carbon atoms-amino, alkane of 1 to 7 carbon atoms-sulfonyl, and cyano. Unsubstituted or substituted cycloalkyl is preferably mono- or bi-cyclic, more preferably monocyclic, cycloalkyl of 3 to 10 carbon atoms, which may include one or more double bonds (eg, in cycloalkenyl) and / or triples (eg, in cycloalkynyl), and is unsubstituted or substituted by one or more, for example, one to four substituents preferably independently selected from those mentioned above as substituents for aryl, especially cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted by up to four substituents selected from alkyl of 1 to 7 carbon atoms, from phenyl (which is unsubstituted or substituted by one or more, especially up to three substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 at 7 carbon atoms-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 carbon atoms, alkanoyl from 1 to 7 carbon atoms, phenyl, halogen, such as chlorine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, phenoxy, amino, alkanoyl of 1 to 7 carbon atoms-amino, carbamoyl, alkane of 1 to 7 carbon atoms-sulfonyl and cyano), from carbamoyl, and from cyano. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl which is unsubstituted or substituted by phenyl, halophenyl, carbamoyl and cyano are preferred. Acyl is preferably aryl-carbonyl unsubstituted or substituted (aryl-C (= 0) -), or -sulfonyl- (aryl-S0 -), heterocyclic-carbonyl (unsubstituted or substituted heterocyclyl-C (= 0) -) or -sulfonyl- (heterocyclyl-S02-), unsubstituted or substituted cycloalkyl-carbonyl (C-cycloalkyl (= 0) -), or -sulfonyl- (cycloalkyl-S02-) ), formyl or (unsubstituted or substituted alkyl, aryl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, heterocyclyl-unsubstituted or substituted alkyl of 1 to 7 carbon atoms, or cycloalkyl-alkyl of 1 to 7 unsubstituted carbon atoms or substituted) -carbonyl or -sulfonyl, or (especially if it is linked with N, S or O) unsubstituted or substituted alkyloxycarbonyl, unsubstituted or substituted aryloxycarbonyl, unsubstituted or substituted heterocyclyloxycarbonyl, unsubstituted cycloalkyloxycarbonyl or replaced, C 1 -C 7 aryloxy-unsubstituted or substituted carbonyl, heterocyclyloxy of 1 to 7 carbon atoms-unsubstituted or substituted carbonyl, C 1 -C 7 -cycloalkyloxy-unsubstituted or substituted carbonyl, or N-mono- or N , N-di- (unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl of 1 to 7 carbon atoms, unsubstituted or substituted heterocyclyl-alkyl of 1 to 7 carbon atoms, cycloalkyl - unsubstituted or substituted alkyl or unsubstituted or substituted alkyl) -aminocarbonyl or -amino-sulfonyl alkyl, with the proviso that the oxy-carbonyl bonding moieties are preferably linked to a carbon atom. nitrogen in the rest of the molecule. Examples of preferred acyl fractions are alkanoyl of 1 to 7 carbon atoms which is unsubstituted or substituted by one or more, especially up to three, for example, one or two fractions independently selected from the group consisting of hydroxyl, amino, N-mono- or N, N-di-alkyl of 1 to 7 carbon atoms-amino and alkanoyl of 1 at 7 carbon-amino atoms, such as acetyl, 2-methyl-propionyl, 2-ethyl-butyryl, 3-methyl-butyryl, 3,3-dimethyl-butyryl, 2,2-dimethyl-propionyl, 3,3- dimethyl-butyryl 3-hydroxy-2,2-dimethyl-propionyl, N, N-dimethyl-amino-acetyl or 2- (N-acetylamino) -4-methyl-butyryl, benzoyl or unsubstituted naphthoyl, or mono-, di- or tri- (halo, alkoxy of 1 to 7 carbon atoms and / or alkyl of 1 to 7 carbon atoms) -substituted, such as 4-methyl-benzoyl, or 3,4-dimethoxy-benzoyl, phenyl or 2- to 7-carbon-alkanoyl naphthyl wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially up to three, alkoxy substituents of 1 to 7 carbon atoms, such as 3-phenyl-propionyl, 2, 2, -dimethyl-2-phenyl-acetyl or 3-ethoxy-phenyl-acetyl, cycloalkyl ilo of 3 to 8 carbon atoms-carbonyl (= cycloalkane-sulfonyl) which is unsubstituted or substituted by one or more, for example, up to four substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms , carbamoyl and cyano, such as cyclopropyl-carbonyl, 2,2,3,3-tetramethyl-cyclopropyl-carbonyl, 1-carbamoyl-cyclopropyl-carbonyl, cyclobutyl-carbonyl or 1-cyano-cyclo-propyl-carbonyl, benzo- [ b] -thiophenylcarbonyl, such as benzo- [b] -thiophene-2-carbonyl, tetrahydro-furanylcarbonyl, such as tetrahydro-furan-2-carbonyl, piperidinyl-carbonyl which is unsubstituted or substituted by 1 to 1 alkanoyl 7 carbon atoms, such as 1- acetyl-piperidin-4-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, such as methylsulfonyl (= methanesulfonyl), (phenyl- or naphthyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, as phenyl-methanesulfonyl, or unsubstituted ((phenyl- or naphthyl) -sulfonyl (mono-, di- or tri-) -substituted by [C 1-7 -alkyl, phenyl, halo-lower alkyl, halogen , oxo-alkyl of 1 to 7 carbon atoms, alkyloxy of 1 to 7 carbon atoms, phenyl-alkoxy of 1 to 7 carbon atoms, halo-alkyloxy of 1 to 7 carbon atoms, phenoxy, alkanoyl of 1 to 7 carbon-amino atoms, alkyl of 1 to 7 carbon atoms-sulfonyl, cyano and / or alkyl of 1 to 7 carbon atoms-sulfonyl], wherein, if more than one substituent is present, the substituents are independently selected from from those mentioned, such as methanesulfonyl, phenyl-methanesulfonyl, phenylsulfonyl (= benzenesulfonyl), naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, toluenes-4-su lfonyl, 4-isopropyl-benzenesulfonyl, bife nil-4-sulfo nyl, 2-trifluoro-methyl-benzenesulfonyl, 3-trifluoro-methyl-benzenesulfonyl, 4-t-rifluoro-methyl-sulfonyl, 4-chloro -benzene-sulfonyl, 3-chloro-benzenesulfonyl, 2-chloro-benzenesulfonyl, 2,4-difluo-benzene-sulfonyl, 2,6-difluoro-benzenesulfonyl, 2,5-dichloro-benzene -sulfonyl, 2,4-dichloro-benzenesulfonyl, 3,4-dichloro-benzenesulfonyl, 3,5-dichloro-benzenesulfonyl, 2,3-dichloro-benzenesulfonyl, 3-methoxy-benzenesulfonyl , 4-me-toxy-benzenesulfonyl, 2,5-dimethoxy-benzenesulfonyl, 2,4-di methoxybenzenesulfonyl, 4-trif luoro-methoxy-benzenesulfonyl, 2-benzyloxy-benzenesulfonyl , 4-phenoxy-benzenesulfonyl, 4- (2-oxo-propyl) -benzenesulfonyl, 3-acetyl-benzenesulfonyl, 4-acetyl- amino-benzenesulfonyl, 4-cyano-benzenesulfonyl, 3-cyan-benzenesulfonyl, 2-cyano-benzenesulfonyl or 4-methanesulfonyl-benzenesulfonyl; halo-thiophene-2-sulfonyl, such as 5-chloro-thiophene-2-sulfonyl, quinolin-sulfonyl, such as quinoline-8-sulfonyl, thiazole-sulfonyl substituted by (C 1 -C 7 -alkanoyl amino and / or alkyl of 1 to 7 carbon atoms), such as 2-acetylamino-4-methyl-thiazole-5-sulfonyl, pyrazole-sulfonyl substituted by (halogen and / or alkyl of 1 to 7 carbon atoms), such as 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonyl, pyridine-sulfonyl, such as pyridine-3-sulfonyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, (unsubstituted or substituted by alkyl of 1 to 7 carbon atoms and / or halogen) -phenyl or naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthylalkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 8 carbon atoms) -amino-carbonyl, such as alkyl of 1 to 7 carbon atoms-amino- carbonyl, especially N-terbutyl-amino-carbonyl, N-phenyl-amino-carbonyl, N- (3-chloro-phenyl) -amino-carbonyl or phenyl-alkyl of 1 to 7 carbon atoms-amino-carbonyl, N-benzyl-amino-carbonyl, or (C 1-7 -alkyl, phenyl, naphthyl, phenyl-C 1-7 -alkyl, naphthyl-C 1-7 -alkyl and / or C 1-6 -alkyl) 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -oxi-carbonyl, for example, alkoxy of 1 to 7 carbon atoms-carbonyl, such as methoxy-ethyl-carbonyl, isopropyloxy-carbonyl, terbutyloxy-carbonyl , isobutyloxy-carbonyl, or 2- (met oxy) -ethoxy-carbonyl, or phenyl-alkyloxy from 1 to 7 carbon atoms-carbonyl, such as benzyloxycarbonyl.
T is methylene (CH2) or preferably carbonyl (C (= 0)). In all the above definitions and below, the person who has experience in the field, without undue experimentation or effort, will be able to recognize which ones are particularly relevant (for example, those that, if present, provide compounds that are sufficiently stable to the manufacture of pharmaceutical products, for example, having a half-life of more than 30 seconds, preferably more than a week) and therefore, preferably are encompassed by the present claims, and that only links and substitutions are encompassed chemically feasible (for example, in the case of double or triple bonds, you can avoid amino or hydroxyl groups that carry hydrogen and the like in order to avoid tautomerism), as well as tautomeric forms where they are present, especially in equilibrium. For example, preferably, for reasons of stability or chemical feasibility, the directly vicinal atoms in the chains are preferably not selected from oxyl plus oxyl, thio plus oxyl, oxyl plus thio, or thio plus thio, except where there is ring systems or the like present that are sufficiently stable. Substituents which are bonded via an O atom (for example, in alkoxy of 1 to 7 carbon atoms) or S which is part of them, are preferably not bound with nitrogen, for example in the rings. The salts are in particular the pharmaceutically acceptable salts of the compounds of the formula I. They can be formed in where there are salt-forming groups present, such as basic or acid groups, which may exist in a form which is at least partially dissociated, for example, in a pH range of 4 to 10 in aqueous solutions, or can be isolated in particular from a solid form, especially crystalline. These salts are formed, for example, as the acid addition salts, preferably with organic or inorganic acids, from the compounds of the formula I, with a basic nitrogen atom (for example, imino or amino), in especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulphonic or sulphonic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, acid maleic, hydroxy-maleic acid, methyl-maleic acid, benzoic acid, methan- or ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalene sulphonic acid, 1,5-naphthalene acid -disulfonic, N-cyclohexyl-sulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid. In the presence of negatively charged radicals, such as carboxyl or sulfo, salts with bases can also be formed, for example, the metal or ammonium salts, such as salts of alkali metals or alkaline earth metals, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) ) -amine, or heterocyclic bases, for example N-ethyl-piperidine or N.N'-dimethyl-piperazine. When a basic group and an acid group are present in the same molecule, a compound of the formula I can also form internal salts. For purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where applicable, included in pharmaceutical preparations) are used, and thereforeThese are the preferred ones. In view of the close relationship between the compounds in free form and in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the compounds or salts thereof, any reference to " "compounds," "starting materials" and "intermediates" hereinbefore and hereinafter, especially the compounds of formula I or their precursors, should be understood to also refer to one or more salts thereof or a mixture of a corresponding free compound and one or more salts thereof, each of which is also intended to include any solvate, metabolic precursor, such as ester or amide of the compound of formula I, or a salt of any one or more thereof, as appropriate and convenient, and if not explicitly mentioned otherwise. You can get different forms of crystal, and then, they are also included. Where the plural form is used for the compounds, starting materials, intermediates, salts, pharmaceutical preparations, diseases, disorders and the like, this is meant to mean one (preferred) or more compounds, salts, pharmaceutical preparations, diseases, disorders, or the like individual wherein the singular or the indefinite article ("a", "an") is used, this is intended to include the plural (eg, also isomers of different configuration of the same compound, e.g. enantiomers in racemates or the like), or preferably the singular ("one"). The compounds of the present invention may possess two or more asymmetric centers, depending on the choice of substituents. Preferred absolute configurations are as indicated herein in a specific manner. However, the present invention encompasses any possible isolated or pure diastereoisomers, enantiomers, or geometric enantiomers, and mixtures thereof, for example, mixtures of enantiomers, such as racemates. As described above, the compounds of the present invention are inhibitors of renin activity, and, therefore, can be used for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy , diseases of the coronary vessels, restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth and / or hyperaldosteronism, and / or other cognitive impairment, Alzheimer's disease, dementia, anxiety states and cognitive disorders, and the like, especially where inhibition of the activity (especially inappropriate) of renin is required. "Inappropriate" activity of renin preferably refers to a condition of a warm-blooded animal, especially a human being, where the renin shows a renin activity that is too high in the given situation (eg, due to one or more of bad regulation, overexpression for example, due to genetic amplification or reconfiguration of chromosomes or infection by microorganisms, such as viruses expressing an aberrant gene, abnormal activity for example, leading to erroneous substrate specificity or a hyperactive renin, eg, produced in normal amounts, too low activity of the pathways that remove the product with renin activity, a high concentration of substrate and / or the like) and / or leads to, or supports a disease or dependent disorder of renin as it is mentioned above and later, for example, by too high a renin activity. This inappropriate renin activity, for example, may comprise a higher than normal activity, or in addition an activity in the normal or even lower than normal range which, however, due to preceding, parallel, and / or subsequent processes , for example, signaling, regulatory effect on other processes, higher concentration of substrate or product, and the like, leads to the direct or indirect support or maintenance of a disease or disorder, and / or to an activity that supports the outbreak and / or the presence of a disease or disorder in any other way. The inappropriate activity of renin may or may not depend in parallel on other mechanisms that support the disorder or disease, and / or the prophylactic or therapeutic effect may or may not include other mechanisms in addition to the inhibition of renin. Therefore "dependent" can be read as "dependent, among other things, "(especially in cases where a disease or disorder is in fact exclusively dependent only on renin) preferably as" mainly dependent ", more preferably as" essentially dependent only. "A disease dependent on a activity (especially inappropriate) of renin can also be one that simply responds to the modulation of renin activity, especially that it responds in a beneficial way (for example, by lowering blood pressure) in the case of inhibition of renin Where a disease or disorder dependent on (= which "depends on", "depending") is mentioned, an activity (especially inappropriate) of renin (as in the definition of "use" in the following paragraph, and also in in which a compound of the formula I is mentioned for use in diagnosis or therapeutic treatment, which is preferably the treatment of a disease or disorder dependent on an inappropriate activity of renin), this preferably refers to any one or more diseases or disorders that depend on an inappropriate activity of the natural renin and / or one or more altered or mutated forms thereof. When subsequently or in the foregoing, the term "use" (as a verb or noun) is mentioned (in relation to the use of a compound of formula I or of a pharmaceutically acceptable salt thereof, or a method of use thereof), it (if not stated in a different way or to be read differently in the context) includes any one or more of the following embodiments of the invention, respectively (if not otherwise mentioned): use in the treatment of a disease or disorder that depends on an activity (especially inappropriate) of renin, the use for the manufacture of pharmaceutical compositions for use in the treatment of a disease or disorder that depends on an activity (especially inappropriate) of renin; a method of using one or more compounds of formula I in the treatment of a disease or disorder that depends on an activity (especially inappropriate) of renin; a pharmaceutical preparation, which comprises one or more compounds of the formula I for the treatment of a disease or disorder depending on a (especially inappropriate) activity of the renin; and one or more compounds of formula I for use in the treatment of a disease or disorder in a warm-blooded animal, especially a human being, preferably a disease that depends on a (particularly inappropriate) activity of renin; as appropriate and convenient, if not mentioned otherwise. The terms "treat", "treatment" or "therapy" refer to prophylactic treatment (eg, delay or prevention of the establishment of a disease or disorder), or preferably therapeutic (including, but not limited to, preventive, delayed establishment and / or progress, palliative, curator, symptom reliever, symptom reducer, patient condition reducer, renin modulator, and / or renin inhibitor) of said diseases or disorders, especially one or more diseases or disorders mentioned above or later. Preferred embodiments according to the invention Preferred groups of embodiments of the invention mentioned below, should not be considered as exclusive, but rather, for example, in order to replace the general expressions or symbols with more specific definitions, the parts of these groups of compounds can be exchanged using the definitions given above, or can be omitted, as appropriate, and each of the more specific definitions, independently of any others, can be entered independently of, or together with, one or more more specific, different definitions, to replace other expressions or more general symbols. The invention preferably relates to a compound of the formula I, wherein the TN R 1 R 2 and N R 3 R 4 fractions are linked in the cis configuration (as the pure isomer or as a mixture of the cis isomers) or in an alternative manner , wherein these fractions are linked in the trans configuration (as the pure isomer or as a mixture of the trans isomers) with respect to the central piperidine ring. The invention, therefore, more preferably refers to a compound of formula I as defined hereinbefore or later herein, which has the configuration shown in the following formula IA: or a salt (preferably pharmaceutically acceptable salt) thereof, or, alternatively, the configuration shown in the following formula IB: or a salt (preferably pharmaceutically acceptable salt) thereof, wherein, in formula IA and in formula IB, R 1, R 2, T, R 3 and R 4 are as defined above or below for a compound of formula I . Alternatively and also more preferably, the invention relates to a compound of formula I as defined hereinabove or later herein, which has the configuration shown in the following IC formula: or a pharmaceutically acceptable salt thereof, or, alternatively, the configuration shown in the following formula I D: or a salt (preferably pharmaceutically acceptable) thereof, wherein, in the formula IC and in the formula I D, R1, R2, T, R3 and R 4 are as defined above or below for a compound of the formula I. In a first preferred embodiment, the invention relates in particular to a compound of the formula I, wherein: R 1 is hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; R2 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl; R3 is hydrogen or unsubstituted or substituted alkyl, R4 is unsubstituted or substituted alkyl, or acyl; and T is carbonyl (C (= 0)); or a salt (preferably pharmaceutically acceptable) thereof; wherein, preferably unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl and / or acyl are as defined above as preferred definitions. Much more preferred is a compound of the formula I, wherein: R 1 is hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, R 2 is phenyl -alkyl of 1 to 7 carbon atoms, naphthyl-alkyl 1 to 7 carbon atoms, di- (phenyl) -alkyl of 1 to 7 carbon atoms, indenyl-alkyl of 1 to 7 carbon atoms, (phenyl- cycloalkyl of 3 to 8 carbon atoms) -alkyl of 1 to 7 carbon atoms, (phenyl) - (pyridyl) -alkyl of 1 to 7 carbon atoms, indolyl-alkyl of 1 to 7 carbon atoms, 4H-benzo -l, 41-oxazin-3-on-yl, (alkoxy of 1 to 7 carbon atoms) -di- (phenyl) -alkyl of 1 to 7 carbon atoms, or (alkoxy of 1 to 7 carbon atoms- carbonyl) -di- (phenyl) -alkyl of 1 to 7 carbon atoms, wherein each phenyl, naphthyl, pyridyl, indolyl or 4H-benzo- [1,4] -oxazin-3-on-yl mentioned for R2 up to now, it is unsubstituted or substituted by one or more, especially up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 atoms carbon, phenyl, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R3 is hydrogen, alkyl of 1 to 7 carbon atoms or phenylalkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, especially up to three, fractions independently selected from the group consisting of alkyl from 1 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl and cyano; and R 4 is phenyl-alkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, for example, up to three, independently selected fractions from the group consisting of halogen and alkoxy of 1 to 7 atoms carbon, such as 2-, 3- or 4-chloro-phenyl-methyl, alkanoyl of 1 to 7 carbon atoms which is unsubstituted or substituted by one or more, especially up to three, for example, one or two fractions independently selected from the group consisting of hydroxyl, amino, N-mono- or N, N-di-alkyl of 1 to 7 carbon atoms-amino and alkanoyl of 1 to 7 carbon atoms-amino, such as acetyl, 2-methyl-propionyl, 2-ethyl- butyryl, 3-methyl-butyryl, 3,3-dimethyl-butyryl, 2,2-di methyl I-pro pion i lo, 3, 3-dimet i I-bu ti ryl, 3-hydroxy-2, 2- di methi I -propionyl, N, N-dimethylaminoacetyl, 2- (N -acet-il-amino) -4-methyl-butyryl, benzoyl or unsubstituted naphthoyl, or mono-, di- or tri-substituted by (halogen, alkoxy of 1 to 7 carbon atoms, and / or alkyl of 1 to 7 carbon atoms), such as 4-methyl-benzoyl or 3,4-dimethoxy-benzoyl, phenyl- or naphthyl-alkanoyl of 2 to 7 carbon atoms, wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially up to three, alkoxy substituents of 1 to 7 carbon atoms, such as 3-phenyl-propionyl, 2,2, -dimethyl- 2-phenyl-acetyl or 3-ethoxy-phenyl-acetyl, cycloalkyl of 3 to 8 carbon atoms-carbonyl (= cycloalkane-carbonyl) which is unsubstituted or substituted One or more, for example, up to four substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, carbamoyl and cyano, such as cyclopropyl-carbonyl, 2, 2, 3, 3-tetramethyl I-cyclopropylcarboyl, or 1-carbamoyl-cyclopropylcarbonyl, cyclobutylcarbonyl or 1-cyanopropylcarbonyl, benzo- [b] -thiophenylcarbonyl, such as benzo- [b] -thiophene-2 carbonyl, tetrahydro-furanyl-carbonyl, such as tetrahydro-furan-2- carbonyl, piperidinylcarbonyl which is unsubstituted or substituted by alkanoyl of 1 to 7 carbon atoms, such as 1-acetyl-piperidin-4-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, such as methyl-sulfonyl (= methanesulfonyl), (phenyl- or naphthyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, such as phenyl-methanesulfonyl, or (phenyl-naphthyl) -sulfonyl (unsubstituted or (mono-, di- - or tri-) substituted) by [C 1-7 -alkyl, phenyl, halo-lower alkyl, halogen, oxo-alkyl of 1 to 7 carbon atoms, alkyloxy of 1 to 7 carbon atoms, phenyl-alkoxy 1 to 7 carbon atoms, haloalkyloxy of 1 to 7 carbon atoms, phenoxy, alkanoyl of 1 to 7 carbon atoms, amino of 1 to 7 carbon atoms, sulfonyl, cyano and / or alkyl of 1 to 7 carbon atoms. to 7 carbon-sulfonyl atoms], wherein, if more than one substituent is present, the substituents are independently selected from those mentioned, such as methan-su lfonyl, phenyl-methanesulfonyl, phenylsulfonyl (= benzenesulfonyl), naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, toluene-4-sulfonyl, 4-isopropyl-benzenesulfonyl, biphenyl-4-sulfonyl, 2-trifluoro-methyl-benzenesulfonyl, 3-trif-1-uoro-methyl-benzene-sulphonyl, 4-trifluoromethylsulfonyl, 4-cl or ro-benzene-sulphonyl, 3-chloro-methyl-benzene sulfonyl, 2-chloro-benzenesulfonyl, 2,4-difluoro-benzenesulfonyl, 2,6-difluorobenzenesulfonyl, 2,5-dioxide ro-benzene n-sulfonyl, 2,4- dichloro-benzenesulfonyl, 3,4-dichloro-benzenesulfonyl, 3,5-dichloro-benzenesulfonyl, 2,3-dichloro-benzenesulfonyl, 3-methoxy-benzenesulfonyl, 4-methoxy-benzene sulfonyl, 2,5-di methoxy-benzene-sulfonyl, 2,4-dimethoxy-benzenesulfonyl, 4-trifluoro-methoxy-benzenesulfonyl, 2-benzyloxy- benzenesulfonyl, 4-phenoxy-benzenesulfonyl, 4- (2-oxo-propyl) -benzenesulfonyl, 3-acetyl-benzenesulfonyl, 4-acetyl-amino-benzenesulphonyl, 4-cyanobenzenes sulphonyl, 3-cyano-benzene-sulphonyl, 2-cyano-benzene sulfonyl or 4-methanesulfonyl-benzenesulfonyl; halo-thiophene-2-sulfonyl, such as 5-chloro-thiophene-2-sulfonyl, quinolin-sulfonyl, such as quinoline-8-sulfonyl, thiazole-sulfonyl substituted by (C 1 -C 7 -alkanoyl amino and / or alkyl of 1 to 7 carbon atoms), such as 2-acetylamino-4-methyl-thiazole-5-sulfonyl, pyrazole-sulfonyl substituted by (halo and / or alkyl of 1 to 7 carbon atoms), such as 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonyl, pyridine sulfonyl, such as pyridine-3-sulfonyl, N-mono- or N, N-di- (alkyl of 1 to 7 atoms carbon, phenyl or naphthyl (unsubstituted or substituted by alkyl of 1 to 7 carbon atoms and / or halogen), phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 at 8 carbon atoms) -aminocarbonyl, such as alkyl of 1 to 7 carbon atoms-amino-carbonyl, especially N-terbutyl-amino-carbonyl, N-phenyl-amino-carbonyl, N- (3-chloro -phenyl) -amino-carbonyl or phenyl-alkyl of 1 to 7 carbon atoms-amino-carbonyl, in esp N-benzyl-amino-carbonyl, or (C 1-7 -alkyl, phenyl, naphthyl, phenyl-C 1-7 -alkyl, naphthyl-C 1-7 -alkyl and / or C 1-6 -alkyl) 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -oxi-carbonyl, for example, alkoxy of 1 to 7 carbon atoms-carbonyl, such as methoxy-ethyl-carbonyl, isopropyloxy-carbonyl, terbutyloxy-carbonyl , isobutyloxy-carbonyl or 2- (methoxy) -ethoxy- carbonyl, or phenyl-alkyloxy of 1 to 7 carbon atoms-carbonyl, such as benzyloxycarbonyl; and T is carbonyl; or a salt (preferably pharmaceutically acceptable) thereof. Preferred Definitions for R1 Preferably, R1 is hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; more preferably hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, When R 1 is unsubstituted or substituted alkyl, it is preferably alkyl of 1 to 7 atoms of carbon, more preferably alkyl of 1 to 4 carbon atoms, such as methyl or ethyl. When R1 is cycloalkyl, it is preferably cycloalkyl of 3 to 8 carbon atoms, such as preferably cycloalkyl of 3, 4, 5, and 6 carbon atoms, more preferably cyclopropyl. When R1 is phenyl-alkyl of 1 to 7 carbon atoms, it is preferably benzyl. When R1 is phenyl-alkyl of 1 to 7 carbon atoms, R2 is preferably alkyl substituted by phenyl as defined herein. Preferred Definitions for R2 Preferably, R2 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl, more preferably phenyl- alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, di- (phenyl) -alkyl of 1 to 7 carbon atoms, indenyl-alkyl of 1 to 7 carbon atoms, (phenyl-cycloalkyl) of 3 to 8 carbon atoms) -alkyl of 1 to 7 carbon atoms, (phenyl) - (pyridyl) -alkyl of 1 to 7 carbon atoms, i ndoli I-alkyl of 1 to 7 carbon atoms, 4H- benzo- [1,4] -oxazin-3-on-yl, (alkoxy of 1 to 7 carbon atoms) -di- (phenyl) -alkyl of 1 to 7 carbon atoms or (alkoxy of 1 to 7 carbon atoms) carbon-carbonyl) -di- (phenyl) -alkyl of 1 to 7 carbon atoms, wherein each phenyl, naphthyl, pyridyl, indolyl or 4H-benzo- [1,4] -oxazin-3-on-yl mentioned for R2 up to now, is unsubstituted or substituted by one or more, especially up to three, fractions, preferably independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl from 1 to 7 carbon atoms, phenyl, halogen, hydroxy it, alkoxy of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms. Preferred definitions for T Preferably T is carbonyl (C (= 0)). Preferred definitions for R3 Preferably, R3 is hydrogen or unsubstituted or substituted alkyl; more preferably hydrogen, alkyl of 1 to 7 carbon atoms, phenyl-alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, wherein phenyl or cycloalkyl are unsubstituted or replaced by one or more, especially up to three, fractions independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, carboxyl, alkoxy of 1 to 7 carbon atoms carbonyl and cyano; still more preferably hydrogen, alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, especially up to three, fractions independently selected from the group that it consists of alkyl of 1 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl and cyano; more preferably R3 is hydrogen, methyl, isobutyl, benzyl or -CH2-cyclopropyl. More preferably R3 is hydrogen. When R3 is unsubstituted or substituted alkyl, it is preferably alkyl of 1 to 7 carbon atoms, more preferably alkyl of 1 to 4 carbon atoms. The alkyl moiety can be substituted as described herein, preferably by phenyl or cycloalkyl of 3 to 7 carbon atoms, wherein phenyl or cycloalkyl are unsubstituted or substituted. When R3 is phenyl-alkyl of 1 to 7 carbon atoms, then R4 is preferably unsubstituted or substituted alkyl, such as phenyl-alkyl of 1 to 7 carbon atoms, or acyl, such as alkyl of 1 to 7 carbon atoms -carbonyl, or unsubstituted or substituted cycloalkyl-carbonyl. When R3 is alkyl of 1 to 7 carbon atoms, then R4 it is preferably unsubstituted or substituted alkyl, such as phenylalkyl of 1 to 7 carbon atoms, or acyl, such as alkyl of 1 to 7 carbon atoms-carbonyl, unsubstituted or substituted aryl-sulfonyl, N-mono- or N, N -di- (unsubstituted or substituted aryl-alkyl of 1 to 7 carbon atoms) -amino-carbonyl or unsubstituted or substituted cycloalkyl-carbonyl. Preferred definitions for R 4 Preferably, R 4 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; such as unsubstituted or substituted alkyl, or acyl, still more preferably phenylalkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, for example, up to three, independently selected fractions from the group consisting of halogen and alkoxy of 1 to 7 carbon atoms, especially 2-, 3- or 4-chlorophenyl-methyl, alkanoyl of 1 to 7 carbon atoms which is unsubstituted or substituted by one or more, in particular up to three, for example, one or two fractions independently selected from the group consisting of hydroxyl, amino, N-mono- or N, N-di-alkyl of 1 to 7 carbon atoms-amino and alkanoyl of 1 to 7 carbon atoms -amino, especially acetyl, 2-methyl-propionyl, 2-ethyl-butyl, 3-methyl-butyryl, 3,3-dimethyl-butyryl, 2,2-dimethyl-propionyl, 3, 3-dimet i - buyl, 3-hydroxy-2,2-di methyl-propionic acid, N, N-dimethyl-amino-acetyl, 2- (N-acetylamino) -4-methyl-butyryl, benzoyl or naphtho unsubstituted, or mono-, di- or tri-substituted by (halogen, 1-alkoxy) to 7 carbon atoms, and / or alkyl of 1 to 7 carbon atoms), especially 4-methyl-benzoyl or 3,4-dimethoxy-benzoyl, phenyl- or naphthyl-alkanoyl of 2 to 7 carbon atoms, in where phenyl or naphthyl is unsubstituted or substituted by one or more, especially up to three, alkoxy substituents of 1 to 7 carbon atoms, especially 3-phenyl-propionyl, 2,2, -dimethyl-2-phenyl-acetyl or 3-ethoxy-phenyl-acetyl, cycloalkyl of 3 to 8 carbon atoms-carbonyl (= cycloalkane-carbonyl) which is unsubstituted or substituted by one or more, for example, up to four substituents independently selected from the group consisting of alkyl from 1 to 7 carbon atoms, carbamoyl and cyano, especially cyclopropyl-carbonyl, 2,2,3,3-tetramethyl-cyclopropyl-carbonyl, 1-carbamoyl-cyclopropyl-carbonyl, cyclobutyl-carbonyl or 1-cyano-cyclopropyl- carbonyl, benzo- [b] -thiophenyl-carbonyl, especially benzo- [b] -thiophene-2-carbonyl, tetrahydro-furanyl-carbonyl, in particular tetrahy idro-furan-2-carbonyl, piperidinyl-carbonyl which is unsubstituted or substituted by alkanoyl of 1 to 7 carbon atoms, such as 1-acetyl-piperidin-4-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, as methyl sulfonyl, (phenyl- or naphthyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, especially phenyl-methanesulfonyl, or (phenyl- or naphthyl) -sulfonyl (unsubstituted or (mono-, di- or tri-) substituted by [C 1-7 alkyl, phenyl, halo-lower alkyl, halogen, oxo-alkyl of 1 to 7 carbon atoms, alkyloxy of 1 to 7 carbon atoms, phenyl-alkoxy of 1 to 7 carbon atoms, halo-alkyloxy of 1 to 7 carbon atoms, phenoxy, alkanoyl of 1 to 7 carbon atoms amino, alkyl of 1 to 7 carbon atoms-sulfonyl, cyano and / or alkyl of 1 to 7 carbon atoms-sulfonyl]), wherein, if more than one substituent is present, the substituents are independently selected from those mentioned, especially methane-sulfonyl, phenyl-methanesulfonyl, phenylsulfonyl, naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, toluene-4-sulfonyl, 4-isopropyl-benzenesulfonyl, biphenyl-4-sulfonyl, 2-trifluoro-methyl-benzenesulfonyl, 3-trifluoromethyl-benzenesulfonyl, 4-tri-fluoro-methyl-sulfonyl, 4-chloro-benzenesulfonyl, 3-chloro-benzenesulfonyl, 2-chloro-benzene -sulfonyl, 2,4-difluoro-benzenesulfonyl, 2,6-difluoro-benzenesulfonyl, 2,5-dichloro-benzenesulfonyl, 2,4-dichloro-benzenesulfonyl, 3,4-dichlorobenzene -sulfonyl, 3,5-dichloro-benzenesulfonyl, 2,3-dichloro-benzenesulfonyl, 3-methoxy-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 2,5-di methoxybenzenesulfonyl, 2,4-dimethoxy-benzenesulfonyl, 4- trifluoromethoxy-benzenesulfonyl, 2-benzyl oxy-benzenesulfonyl, 4-phenoxy-benzenesulfonyl, 4- (2-oxo-propyl) -benzenesulfonyl, 3-acetyl-benzenesulfonyl, 4-acetyl-amino-benzenesulfonyl, 4-cyano- benzenesulfonyl, 3-cyano-benzenesulfonyl, 2-cyanobenzenesulfonyl or 4-methanesulfonylbenzenesulfonyl; halo-thiophene-2-sulfonyl, in particular 5-chloro-thiophene-2-sulfonyl, quinolin-sulfonyl, in particular quinoline-8-sulfonyl, thiazole-sulfonyl substituted by (alkanoyl of 1 to 7 carbon-amino atoms and / or alkyl of 1 to 7 carbon atoms), especially 2-acetylamino-4-methyl-thiazole-5-sulfonyl, pyrazole-sulfonyl substituted by (halogen and / or alkyl of 1 to 7 carbon atoms), in 5-chloro-1,3-dimethyl-1H-pyrazol-4-sulfonyl, pyridine-sulfonyl, such as pyridine-3-sulfonyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl or naphthyl (unsubstituted or substituted by alkyl of 1 to 7 carbon atoms and / or halogen), phenyl -alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 8 carbon atoms) -amino-carbonyl, especially alkyl of 1 to 7 carbon atoms-amino-carbonyl, in particular N-terbutyl-amino-carbonyl, N-phenyl-amino-carbonyl, N- (3-chloro-phenyl) -amino-carbonyl or phenyl-alkyl of 1 to 7 carbon-amino-carbonyl, in particular N -benzylaminocarbonyl, or (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -oxi-carbonyl, for example, alkoxy of 1 to 7 carbon atoms-carbonyl, in particular terbutyloxycarbonyl or isobutyloxycarbonyl, or phenyl-alkyloxycarbonyl of 1 to 7 carbon atoms. In a first embodiment, R4 is acyl. Preferred examples are selected from the group consisting of (a) to (o): (a) unsubstituted or substituted mono- or bi-cyclic carbonyl The preferred examples of the aryl fraction include aryl of 6 to 22 atoms of mono- or bi-cyclic carbon, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, condensed with the other aromatic ring, especially phenyl, indanyl, indenyl, 1, 2,3,4- tetrahydro-naphthyl or naphthyl, more preferably phenyl. When the aryl fraction is substituted, it is preferably mono- or di-substituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, such as methyl, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, halogen, such as Cl, -O-alkylene from 1 to 7 carbon atoms-O-alkyl, such as 0-C3H6OCH3, hydroxyl, phenyl- or naphthyl-oxyl phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted or substituted, unsubstituted preference, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano, unsubstituted or substituted heterocyclyl, preferably unsubstituted, or unsubstituted or substituted heterocyclyl-alkyl of 1 to 4 carbon atoms, preferably unsubstituted , such as heterocyclyl-CH2, wherein the heterocyclyl fraction in each case is preferably 5 or 6 membered monocyclic heterocyclyl, preferably containing a nitrogen and / or oxygen atom, such as tetrahydro-furanyl or tetrahydro-pyranyl, piperidinyl, pyrrolidinyl, piperazinyl or morfol inyl, more preferably alkyl of 1 to 7 carbon atoms and / or -O-alkyl of 1 to 7 carbon atoms. (b) Unsubstituted or substituted mono- or bi-cyclic heterocyclic carbonyl Preferred examples for the heterocyclyl fraction are mono- or bi-cyclic rings. Preferred ring systems are from 3 to 14, more preferably from 5 to 11 members. The heterocyclyl fraction can be saturated, partially saturated, or aromatic ring systems. The heterocyclyl fraction preferably has 1, 2 or 3, more preferably 1 or 2 heteroatoms selected from O, N or S, more preferably O or N. Particularly preferred examples include the 5 or 6 membered rings which preferably contain a nitrogen or oxygen atom, in particular pyrrolidinyl, oxazolyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, furanyl, pyrimidyl, pyridyl , pyrazinyl, isoxazolyl, pyrrolidin-2-onyl, tetrahydro-furanyl, or tetrahydro-pyranyl, in particular tetrahydro-furanyl, or tetrahydropyranyl or pyridyl; or 9- to 11-membered bicyclic ring systems preferably containing at least one nitrogen and / or sulfur atom, in particular indolyl, 2,3-dihydro-benzo- [1,4] -dioxinyl, benzo-furanyl, 4H-benzo- [1,4] -oxazin-3-onyl, benzooxazolyl, benzo- [1, 2,5] -oxadiazolyl, benzimidazolyl or benzothiophenyl, more preferably benzothiophenyl. When the heterocyclyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the heterocyclyl fraction are as defined herein, preferably -alkyl of 1 to 7 carbon atoms, such as methyl, halogen, hydroxyl, alkanoyl of 1 to 7 carbon atoms, such as acetyl, phenyl unsubstituted or substituted, preferably unsubstituted, phenyl- or naphthyl-oxo-phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted or unsubstituted or unsubstituted, preferably unsubstituted or unsubstituted cycloalkyl of 3 to 8 carbon atoms or substituted, preferably unsubstituted, such as cyclopropyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano, unsubstituted or substituted heterocyclyl, preferably unsubstituted, or heterocyclyl-alkyl of 1 to 4 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as heterocyclyl-CH2, wherein the heterocyclyl fraction in each case is preferably 5- or 6-membered monocyclic heterocyclyl, preferably containing a nitrogen and / or oxygen atom, such as tetrahydro-furanyl or tetrahydro-pyranyl , piperidinyl, pyridyl, pyrrolidinyl, piperazinyl or morpholinyl, more preferably alkanoyl of 1 to 7 carbon atoms, cyano, or pyridyl. More preferably, the heterocyclyl fraction is unsubstituted or mono-substituted, as described above. (c) Mono- or bi-cyclic unsubstituted or substituted cycloalkylcarbonyl Preferred examples for the cycloalkyl fraction are monocyclic rings, preferably cycloalkyl of 3 to 8 carbon atoms, more preferably cycloalkyl of 3, 4, 5, and 6 carbon atoms. The cycloalkyl fraction can be substituted or unsubstituted. When the cycloalkyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the cycloalkyl fraction are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably unsubstituted, phenyl- or unsubstituted or substituted naphthyl-oxyl, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, unsubstituted or substituted heterocyclyl, preferably unsubstituted, or heterocyclyl-alkyl of 1 to 4 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as heterocyclyl-CH2, in wherein the heterocyclyl fraction in each case is preferably 5- or 6-membered monocyclic heterocyclyl, preferably containing a nitrogen and / or oxygen atom, such as tetrahydrofuranyl or tetrahydro-pyranyl, piperidinyl, pyridyl, tetrazolyl, pyrrolidinyl, piperazinyl or morpholinyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carbamoyl, alkanoyl of 1 to 7 carbon atoms-amino, carboxyl, and cyano, wherein suitable phenyl substituents include alkyl of 1 to 7 carbon atoms. carbon, such as methyl, -O-alkyl of 1 to 7 carbon atoms, halo-alkyl of 1 to 7 carbon atoms, halogen, hydroxyl and amino, more preferably cycloalkyl is unsubstituted or substituted by carbamoyl, cyano, pyridyl, tetrazolyl or phenyl. (d) Unsubstituted or substituted alkylcarbon Preferred examples for the alkyl moiety are branched or straight chain alkyl of 1 to 7 carbon atoms, which may be substituted or unsubstituted. In one embodiment, the alkyl moiety is branched alkyl, such as isopropyl, isobutyl, secondary butyl or tertiary butyl, isopentyl, 1-ethyl-propyl, 2,2-dimethyl-propyl, 1,2-dimethyl-propyl, 1- ethyl-2-methyl-propyl, or 3-methyl-butyl. In another embodiment, the alkyl moiety is straight chain alkyl, such as methyl, ethyl, normal propyl, normal butyl or normal pentyl, preferably methyl, ethyl or normal propyl. When the alkyl moiety is substituted, it is preferably mono-, di- or tri-substituted, more preferably mono-substituted. Suitable substituents for the alkyl moiety are as defined herein, O-alkyl preference of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, unsubstituted or substituted phenyl- or naphthyl-oxy, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted , nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, amino-carbonyl, amino-carbonyl N-mono- or N, N-di- substituted, such as CONHMe, amino N-mono- or N, N-di-substituted, such as NMe2, carboxyl, alkyloxy of 1 to 7 carbon atoms-carbonyl, such as COOMe, cyano, heterocyclyl-alkyl of 1 to 4 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as heterocyclyl-CH2, wherein the heterocyclyl fraction in each case is preferably 5- or 6-membered monocyclic heterocyclyl, preferably containing a nitrogen and / or oxygen atom, such as tetrahydro-furanyl or tetrahydro-pyranyl, piperidinyl, pyridyl, tetrazolyl, pyrrolidinyl, piperazinyl or morpholinyl, and wherein suitable phenyl or heterocyclyl substituents include alkyl of 1 to 7 carbon atoms, such as methyl, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms , halogen, hydroxyl and amino, preferably alkyl of 1 to 7 carbon atoms, and wherein suitable amino substituents include alkyl of 1 to 7 carbon atoms, such as methyl, phenyl or cyclopropyl, preferably alkyl of 1 to 7 carbon atoms. More preferably, the alkyl moiety is unsubstituted, or mono-substituted by -O-alkyl of 1 to 7 carbon atoms, hydroxyl, alkanoyl of 1 to 7 carbon-amino atoms, phenyloxy unsubstituted or substituted, tetrahydro-pyranyloxy, pyridyl loxy or amino N-mono- or N, N-di-substituted. (e) Aryl-alkyl of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl Preferably aryl-alkyl is aryl-alkyl of 1 to 6 carbon atoms, more preferably aryl-alkyl of 1 to 4 carbon atoms, in particular aryl-CH-, aryl-CH2CH2-, aryl-CH (CH3) -, aryl-CH2CH (CH3) - or aryl-C (CH3) 2-, more preferably aryl-CH2-. The alkyl fraction, in particular when aryl-alkyl is aryl-CH2- or aryl-CH2CH2-, may be substituted, preferably mono-substituted. Examples of preferred substituents include O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, carboxyl, and cyano, more preferably alkanoyl of 1 to 7 carbon atoms-amino, O-alkyl of 1 to 4 carbon atoms or hydroxyl. Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, in phenyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl or naphthyl, more preferably phenyl or naphthyl. When the aryl moiety is substituted, it is preferably mono-, di- or tri-substituted. In particular, phenyl is preferably unsubstituted, mono-, di- or tri-substituted, and naphthyl is preferably unsubstituted. In a embodiment, phenyl is preferably unsubstituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, as CF3, halogen, such as Cl or F, -O-alkylene of 1 to 7 carbon atoms-O-alkyl, such as 0-C3H6OCH3, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably substituted, phenyl- or naphthyl unsubstituted or substituted, preferably unsubstituted, phenyl-0-naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, carboxyl, and cyano. Suitable substituents for the phenyl and naphthyl substituent on the aryl moiety of the aryl alkylcarbon include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon, halogen, hydroxyl and amino atoms. More preferably, the aryl fraction is unsubstituted or substituted by -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, substituted phenyl, alkanoyl of 1 to 7 carbon atoms-amino and / or halogen. (f) Heterocyclyl-C 1-7 -alkyl or unsubstituted or substituted bicyclic carbonyl. Preferably heterocyclyl-alkyl is heterocyclyl-C 1-6 -alkyl, more preferably heterocyclyl-C 1-6 -alkyl. 4 carbon atoms, in particular heterocyclyl-CH2-, heterocyclyl- CH2CH2- or heterocyclyl-CH2C (CH3) 2-, more preferably heterocyclyl-CH2-. Preferred examples for the heterocyclyl fraction are the mono- or bi-cyclic rings. Preferred ring systems are from 3 to 14, preferably from 5 to 11 members. The heterocyclyl fraction can be saturated, partially saturated or aromatic, in particular if a monocyclic fraction, aromatic or saturated rings are contemplated, or, in particular if a bicyclic fraction is contemplated, aromatic or partially saturated ring systems, in particular where one of the rings is aromatic and the other is saturated or partially saturated. The heterocyclyl fraction preferably has 1, 2 or 3, more preferably 1 or 2 heteroatoms selected from O, N or S, more preferably O or N. Particularly preferred examples include the 5- or 6-membered rings containing preferably a nitrogen or oxygen atom, in particular pyrrolidinyl, oxazolyl, pyrimidyl, pyridyl, pyrazinyl, isoxazolyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, furanyl, tetrahydro-furanyl, or tetrahydro-pyranyl; or 9- to 11-membered bicyclic ring systems preferably containing at least one nitrogen and / or oxygen atom, in particular 4H-benzo- [1,4] -oxazin-3-onyl, benzooxazolyl, indolyl, , 3-dihydro-benzo- [1,4] -dioxinyl, chromanyl, 2H-chromenyl, 3,4-dihydro-1 H -quinolin-2-onyl, benzo- [d] -isoxazolyl, 4,5,6, 7-tetrahydro-benzo- [d] -isoxazolyl, 3a, 4,5,6,7,7a-hexahydro-benzo- [d] -isoxazolyl, 1, 4, 5, 6, -tetrahydro-cyclopenta-pyrazolyl, 3,4-dihydro-2H-benzo- [b] [1,4] -dioxepinyl, benzo-furanyl, benzo- [1, 2,5] -oxadiazolyl, benzimidazolyl or 3,4-dihydro-2H-benzo- [1,4] -oxazinyl, more preferably pyrrolidinyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, furanyl, tetrahydro-furanyl, tetrahydro-pyranyl, 4H-benzo- [1,4] -oxazin-3-onyl or benzooxazolyl, more preferably tetrahydro-pyranyl or pyridyl. When the heterocyclyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the heterocyclyl fraction are as defined herein, preferably -alkyl of 1 to 7 carbon atoms, such as methyl, halogen, hydroxyl, alkanoyl of 1 to 7 carbon atoms, unsubstituted or substituted phenyl, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxy, preferably unsubstituted, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as cyclopropyl, nitro, amino , aminoalkyl of 1 to 7 carbon atoms, carboxyl, cyano, more preferably -alkyl of 1 to 7 carbon atoms. Suitable phenyl substituents include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, hydroxyl and amino. More preferably, the heterocyclyl fraction is unsubstituted or is mono-substituted with -alkyl of 1 to 7 carbon atoms. (g) Cycloalkyl-alkyl of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl Preferably cycloalkyl-alkyl is cycloalkyl-alkyl of 1 to 6 carbon atoms, more preferably cycloalkyl-alkyl of 1 to 4 carbon atoms, in particular cycloalkyl-CH2-, cycloalkyl-CH2CH2- or cycloalkyl-CH2C (CH3) 2-, more preferably cycloalkyl-CH2-. The alkyl moiety can be substituted, preferably mono-substituted, including on the carbon atom in which the cycloalkyl moiety is attached. Examples of preferred substituents include O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, nitro, amino, aminoalkyl of 1 to 7 carbon atoms, carboxyl, and cyano, more preferably O-alkyl of 1 to 4 carbon atoms or hydroxyl. Preferred examples for the cycloalkyl fraction are monocyclic rings, preferably cycloalkyl of 3 to 7 carbon atoms, more preferably cycloalkyl of 3, 5, and 6 carbon atoms. The cycloalkyl fraction can be substituted or unsubstituted. Cycloalkyl of 3 carbon atoms is preferably unsubstituted and cycloalkyl of 5 and 6 carbon atoms is preferably unsubstituted or substituted. When the cycloalkyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the cycloalkyl fraction are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, unsubstituted or substituted phenyl, naphthyl, phenyl- or naphthyl-oxyl unsubstituted or substituted, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, -NHCOEt or -NHCOCHCH 3) 2, carboxyl, and cyano, more preferably amino, O-alkyl of 1 to 4 carbon atoms or hydroxyl. (h) Unsubstituted or substituted alkyloxycarbonyl Preferred examples for the alkyl moiety are branched or straight chain alkyl of 1 to 7 carbon atoms, which may be substituted or unsubstituted. In one embodiment, the alkyl moiety is branched alkyl, such as isopropyl, isobutyl, secondary butyl or tertiary butyl, isopentyl, 1-ethyl-1-propyl, 2,2-dimethyl-propyl and 1,2-dimethyl-propyl. In another embodiment, the alkyl moiety is straight chain alkyl, such as methyl, ethyl, normal propyl, normal butyl or normal pentyl, preferably methyl or ethyl. When the alkyl moiety is substituted, it is preferably mono-, di- or tri-substituted, more preferably mono-substituted. Suitable substituents for the alkyl moiety are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, unsubstituted or substituted phenyl- or naphthyl-oxy, phenyl- or unsubstituted or substituted, preferably unsubstituted, naphthyl-alkyloxy of 1 to 7 carbon atoms, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-amino, such as -NHCOMe, amino carbonyl, amino-carbonyl N-mono- or N, N-di-substituted, such as CONHMe, carboxyl, alkyloxy of 1 to 7 carbon atoms-carbonyl, such as COOMe, and cyano, wherein the substituents of phenyl or Suitable naphthyl include alkyl of 1 to 7 carbon atoms, such as methyl, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of from 1 to 7 carbon atoms, halogen, hydroxyl and amino, preferably alkyl of 1 to 7 carbon atoms, and wherein the amino substituents Suitable include alkyl of 1 to 7 carbon atoms, such as methyl, phenyl or cyclopropyl, preferably alkyl of 1 to 7 carbon atoms. More preferably, the alkyl moiety is unsubstituted or mono-substituted by -O-alkyl of 1 to 7 carbon atoms. (i) Unsubstituted or substituted mono- or bicyclic heterocyclyloxycarbonyl Preferred examples for the heterocyclyl fraction are mono- or bi-cyclic rings. Preferred ring systems are from 3 to 14, preferably from 5 to 11 members. The heterocyclyl fraction can be saturated, partially saturated or aromatic, in particular if a monocyclic fraction is contemplated, aromatic or saturated rings, more preferably saturated, or, in particular if a bicyclic fraction is contemplated, aromatic or partially saturated ring systems, in particular where one of the The rings are aromatic and the other is saturated or partially saturated. The heterocyclyl fraction preferably has 1, 2 or 3, more preferably 1 or 2 heteroatoms selected from O, N or S, more preferably O or N. Particularly preferred examples include the 5- or 6-membered rings containing preferably a nitrogen or oxygen atom, in particular pyrrolidinyl, oxazolyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, furanyl, pyrimidyl, pyridyl, pyrazinyl, isoxazolyl, pyrrolidin-2-onyl, tetrahydro-furanyl, or tetrahydro-pyranyl; more preferably tetrahydro-furanyl or tetrahydro-pyranyl. When the heterocyclyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the heterocyclyl fraction are as defined herein, preferably -alkyl of 1 to 7 carbon atoms, such as methyl, halogen, hydroxyl, alkanoyl of 1 to 7 carbon atoms, unsubstituted or substituted phenyl, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxy, preferably unsubstituted, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted , preferably unsubstituted, such as cyclopropyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano, more preferably phenyl, -alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 8 carbon atoms. carbon. Suitable phenyl and cycloalkyl substituents include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, hydroxyl and amino. More preferably, the heterocyclyl fraction is unsubstituted. (j) Aryl-alkyloxy of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl Preferably arylalkyl is aryl-alkyl of 1 to 6 carbon atoms, more preferably aryl-alkyl of 1 to 4 carbon atoms, in particular aryl-CH2-, aryl-CH2CH2-, aryl-CH (CH3) -, aryl- CH2CH (CH3) - or aryl-CH (CH2CH3) -, more preferably aryl-CH-. Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, in special phenyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl or naphthyl, more preferably phenyl. When the aryl moiety is substituted, it is preferably mono-, di- or tri-substituted. In one embodiment, phenyl is preferably unsubstituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, as CF3, halogen, such as Cl or F, -O-alkylene of 1 to 7 carbon atoms-O-alkyl, such as 0-C3H6OCH3, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably substituted, phenyl- or naphthyl unsubstituted or substituted, preferably unsubstituted, phenyl- or naphthi-1-alkyloxyl unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, carboxyl, and cyano. Suitable substituents for the phenyl and naphthyl substituent on the aryl moiety of the aryl alkylcarbon include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon, halogen, hydroxyl and amino atoms. (k) N-mono- or N, N-di- (mono- or bi-cyclic aryl unsubstituted or substituted, unsubstituted or substituted mono- or bi-cyclic cycloalkyl, aryl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted or substituted and / or unsubstituted or substituted alkyl) -a mino-car bonyl Preferred examples for the fraction Alkyl of the unsubstituted or substituted I-amino-carbonyl alkyl are branched or straight chain alkyl of 1 to 7 carbon atoms, which may be substituted or unsubstituted. In one embodiment, the alkyl moiety is branched alkyl, such as isopropyl, isobutyl, secondary butyl or tertiary butyl, isopentyl, 1-ethyl-1-propyl, 2,2-dimethyl-propyl and 1,2-dimethyl-propyl, plus preferably tertiary butyl. In another embodiment, the alkyl moiety is straight chain alkyl, such as methyl, ethyl, normal propyl, normal butyl or normal pentyl, preferably methyl or ethyl. When the alkyl moiety is substituted, it is preferably mono-, di- or tri-substituted, more preferably mono-substituted. Suitable substituents for the alkyl moiety are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, phenyl- or naphthyl-oxyl-unsubstituted or substituted, preferably unsubstituted , phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, amino-carbonyl, amino-carbonyl N-mono- or N, N-di-substituted, such as CONHMe, carboxyl, alkyloxy of 1 to 7 carbon atoms-carbonyl, such as COOMe, and cyano. More preferably, the alkyl moiety is unsubstituted. Preferred examples of the aryl moiety of the unsubstituted or substituted arylaminocarbonyl include aryl of 6 to 22 mono- or bi-cyclic carbon atoms, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring , condensed with the other aromatic ring, especially phenyl or naphthyl, more preferably phenyl. When the aryl fraction is substituted, it is preferably mono- or di-substituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, halogen , such as Cl, -O-alkylene of 1 to 7 carbon atoms-O-alkyl, such as 0-C3H6OCH3l hydroxyl, unsubstituted or substituted, preferably unsubstituted phenyl- or naphthyl-oxy, phenyl- or naphthyl-alkyloxy to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano. More preferably aryl is unsubstituted or substituted with Cl. Preferred examples for the cycloalkyl moiety of unsubstituted or substituted cycloalkyl-amino-carbonyl are monocyclic rings, preferably cycloalkyl of 3 to 8 carbon atoms, more preferably cycloalkyl of 3, 4 , 5, 6, and 7 carbon atoms, more preferably cycloalkyl of 6 carbon atoms. The cycloalkyl fraction may be substituted or unsubstituted, preferably unsubstituted. When the cycloalkyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the cycloalkyl fraction are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, unsubstituted or substituted phenyl, naphthyl, phenyl- or naphthyl-oxyl unsubstituted or substituted, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 atoms of carbon-amino, carboxyl, and cyano, more preferably O-alkyl of 1 to 4 carbon atoms or hydroxyl. More preferably cycloalkyl is unsubstituted. Preferably the aryl-alkyl fraction of the unsubstituted or substituted aryl-alkyl-amino-carbonyl is aryl-alkyl of 1 to 6 carbon atoms, more preferably aryl-alkyl of 1 to 4 carbon atoms, in particular aryl-CH 2 - , aryl-CH2CH2-, or aryl-CH (CH2CH3) -, more preferably aryl-CH2-. Preferred examples of the aryl fraction include aryl of 6 to 22 mono- or bicyclic carbon atoms, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, especially phenyl or naphthyl, more preferably phenyl. When the aryl moiety is substituted, it is preferably mono-, di- or tri-substituted. In one embodiment, phenyl is preferably unsubstituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms. carbon, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, such as CF 3, halogen, such as Cl or F, -O-alkylene of 1 to 7 atoms of carbon-O-alkyl, such as 0-C3H6OCH3, hydroxyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, carboxyl, and cyano , more preferably -O-alkyl of 1 to 7 carbon atoms or halogen. It is preferred that the amino-carbonyl group is N-mono- (unsubstituted or substituted mono- or bi-cyclic aryl, unsubstituted or substituted mono- or bi-cyclic cycloalkyl, aryl-alkyl of 1 to 7 carbon atoms mono- or bi-cyclic. - unsubstituted or substituted cyclic, or unsubstituted or substituted alkyl) -aminocarbonyl. (I) Unsubstituted or substituted mono- or bi-cyclic aryl sulfonyl Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, especially phenyl, or naphthyl, more preferably phenyl. When the aryl fraction is substituted, it is preferably mono- or di-substituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, such as methyl or isopropyl, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, such as CF3, haloalkoxy of 1 to 7 carbon atoms, such as OCF3, halogen, such as Cl or F, -O-alkylene of 1 to 7 carbon atoms-O-alkyl, such as OR- C3H6OCH3, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxyl, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as phenyl-CH2-0-, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, such as CH2C (0) Me, alkanoyl of 1 to 7 carbon atoms-amino, such as NHC (0) Me, alkanoyl of 1 to 7 carbon atoms, such as acetyl, carboxyl, alkyl of 1 to 7 carbon atoms-sulfonyl, such as -S ( 0) 2Me, and / or cyano, more preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, halogen, phenyl or unsubstituted or substituted naphthyl, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxyl, preferentially unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, alkanoyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms -amino, alkanoyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-sulfonyl and / or cyano. (m) Unsubstituted or substituted mono- or bi-cyclic heterocyclylsulfonyl The preferred examples for the heterocyclyl fraction are the mono- or bi-cyclic rings. Preferred ring systems are from 3 to 14, preferably from 5 to 11 members. The heterocyclyl fraction can be saturated, partially saturated ring systems, 0 aromatics. The heterocyclyl fraction preferably has 1, 2 or 3, more preferably 1 or 2 heteroatoms selected from O, N or S, more preferably S or N. Particularly preferred examples include the 5- or 6-membered rings containing preferably a nitrogen or sulfur atom, in particular pyrrolidinyl, oxazolyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, pyrimidyl, pyridyl, pyrazinyl, pyrazolyl, isoxazolyl, pyrrolidin-2-onyl, thiazolyl, or thiophenyl, in particular thiophenyl, thiazolyl, pyridyl or pyrazolyl; or 9- to 11-membered bicyclic ring systems preferably containing at least one nitrogen and / or sulfur atom, in particular indolyl, 2,3-dihydro-benzo- [1,4] -dioxinyl, benzo-furanyl, quinolinyl, 4H-benzo- [1,4] -oxazin-3-onyl, benzooxazolyl, benzo- [1, 2,5] -oxadiazolyl, benzimidazolyl or benzo-thiophenyl, more preferably quinolinyl. When the heterocyclyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the heterocyclyl fraction are as defined herein, preferably -alkyl of 1 to 7 carbon atoms, such as methyl, halogen, such as Cl, hydroxyl, alkanoyl of 1 to 7 carbon atoms, as acetyl, alkanoyl 1 to 7 carbon atoms-amino, such as NHC (0) Me, unsubstituted or substituted phenyl, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxy, preferably unsubstituted, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted, preferably unsubstituted, such as cyclopropyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano, more preferably alkanoyl of 1 to 7 carbon atoms, cyano, or pyridyl. More preferably, the heterocyclyl fraction is unsubstituted, or is substituted by alkyl of 1 to 7 carbon atoms, halogen, and / or alkanoyl of 1 to 7 carbon-amino atoms. (n) Aryl-alkyl of 1 to 7 carbon atoms-sulfonyl mono- or bi-cyclic unsubstituted or substituted. Preferably aryl-alkyl is aryl-alkyl of 1 to 6 carbon atoms, more preferably aryl-alkyl of 1 to 4. carbon atoms, in particular aryl-CH2-, aryl-CH2CH2-, aryl-CH (CH3) -, aryl-CH2CH (CH3) - or aryl-CH (CH2CH3) -, more preferably aryl-CH2-. Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, in special phenyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl or naphthyl, more preferably phenyl. When the aryl moiety is substituted, it is preferably mono-, di- or tri-substituted. In one embodiment, phenyl is preferably unsubstituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, as CF3, halogen, such as Cl or F, -O-alkylene of 1 to 7 carbon atoms- O-alkyl, such as 0-C3H60CH3, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably substituted, unsubstituted or substituted phenyl- or naphthyl-oxy, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon-amino atoms, such as -NHCOMe, carboxyl, and cyano. Suitable substituents for the phenyl and naphthyl substituent on the aryl moiety of the aryl alkylcarbon include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon, halogen, hydroxyl and amino atoms. Most preferably, aryl is unsubstituted. (o) unsubstituted or substituted C 1-7 alkyl sulfonyl The preferred examples for the alkyl moiety are branched or straight chain alkyl of 1 to 7 carbon atoms, which may be substituted or unsubstituted. In one embodiment, the alkyl moiety is branched alkyl, such as isopropyl, isobutyl, secondary butyl or tertiary butyl, isopentyl, 1-ethyl-propyl, 2,2-dimethyl-propyl and 1,2-dimethyl-propyl, more preferably tertiary butyl. In another embodiment, the alkyl moiety is straight chain alkyl, such as methyl, ethyl, normal propyl, normal butyl or normal pentyl, preferably methyl or ethyl. When the alkyl moiety is substituted, it is preferably mono-, di- or tri-substituted, more preferably mono-substituted. Suitable substituents for the alkyl moiety are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, unsubstituted or substituted phenyl- or naphthyl-oxy, preferably unsubstituted, phenyl- unsubstituted or substituted, preferably unsubstituted, naphthyl-alkyloxy of 1 to 7 carbon atoms, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-amino, such as -NHCOMe, amino carbonyl, amino-carbonyl N-mono- or N, N-di-substituted, such as CONHMe, carboxyl, alkyloxy of 1 to 7 carbon atoms-carbonyl, such as COOMe, and cyano. More preferably, the alkyl moiety is unsubstituted. In a second embodiment, R 4 is aryl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted mono- or bi-cyclic. Preferably aryl-alkyl is aryl-alkyl of 1 to 6 carbon atoms, more preferably aryl-alkyl of 1 to 4 carbon atoms, in particular aryl-CH2-, aryl-CH2CH2-, aryl-CH (CH3) -, aryl-CH 2 CH (CH 3) - or aryl-CH (CH CH 3) -, more preferably aryl-CH 2 -. Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, in special phenyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl or naphthyl, more preferably phenyl. When the aryl moiety is substituted, it is preferably mono-, di- or tri-substituted. In one embodiment, phenyl is preferably unsubstituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 carbon atoms, such as CF3, halogen , such as Cl or F, -O-alkylene of 1 to 7 carbon atoms-O-alkyl, such as 0-C3H6OCH3, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably substituted, unsubstituted phenyl- or naphthyl-oxyl or substituted, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms -amino, such as -NHCOMe, carboxyl, and cyano. Suitable substituents for the phenyl and naphthyl substituent on the aryl moiety of the aryl alkylcarbon include alkyl of 1 to 7 carbon atoms, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, hydroxyl and amino. Most preferably, aryl is unsubstituted. In a third embodiment, R 4 is unsubstituted or substituted mono- or bi-cyclic cycloalkyl. Preferred examples for the cycloalkyl fraction are monocyclic rings, preferably cycloalkyl of 3 to 8 carbon atoms, more preferably cycloalkyl of 3, 4, 5, and 6 carbon atoms, more preferably cycloalkyl of 6 carbon atoms. The cycloalkyl fraction can be substituted or unsubstituted. When the cycloalkyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the fraction of cycloalkyl are as defined herein, preferably O-alkyl of 1 to 4 carbon atoms, such as OMe, halogen, hydroxyl, phenyl or unsubstituted or substituted naphthyl, preferably unsubstituted, unsubstituted phenyl- or naphthyl-oxyl or substituted, preferably unsubstituted, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carbamoyl, alkanoyl of 1 to 7 atoms of carbon-amino, carboxyl, and cyano, wherein suitable phenyl substituents include alkyl of 1 to 7 carbon atoms, such as methyl, -O-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon, halogen, hydroxyl and amino atoms, more preferably cycloalkyl is unsubstituted.
In a fourth embodiment, R 4 is unsubstituted or substituted mono- or bi-cyclic aryl. Preferred examples of the aryl fraction include aryl of 6 to 22 carbon atoms mono- or bi-cyclic, wherein one of the rings of the bicyclic aryl may be a partially or fully saturated ring, fused with the other aromatic ring, in special phenyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl or naphthyl, more preferably phenyl. When the aryl fraction is substituted, it is preferably mono- or di-substituted. Suitable substituents are as defined herein, preferably alkyl of 1 to 7 carbon atoms, such as methyl, -O-alkyl of 1 to 7 carbon atoms, such as OMe, haloalkyl of 1 to 7 atoms carbon, halogen, such as Cl, -O-alkylene of 1 to 7 carbon atoms carbon-O-alkyl, such as 0-C3H6OCH3, hydroxyl, unsubstituted or substituted, preferably unsubstituted phenyl- or naphthyl-oxy, phenyl- or naphthyl-alkyloxy of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, nitro , amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano. Most preferably, aryl is unsubstituted. In a fifth embodiment, R 4 is unsubstituted or substituted mono- or bi-cyclic heterocyclyl. Preferred examples for the heterocyclyl fraction are the mono- or bi-cyclic rings. Preferred ring systems are from 3 to 14, preferably from 5 to 11 members. The heterocyclyl fraction can be saturated, partially saturated, or aromatic ring systems. The heterocyclyl fraction preferably has 1, 2 or 3, more preferably 1 or 2 heteroatoms selected from O, N or S, more preferably O or N. Particularly preferred examples include the 5- or 6-membered rings containing preferably a nitrogen or oxygen atom, in particular pyrrolidinyl, oxazolyl, pyrrolidin-2-onyl, pyrrolyl, piperidyl, furanyl, pyrimidyl, pyridyl, pyrazinyl, isoxazolyl, pyrrolidin-2-onyl, tetrahydrofuranyl, or tetrahydro-pyranyl, in particular pyrimidyl or pyridyl; or 9 to 11-membered bicyclic ring systems preferably containing at least one nitrogen and / or sulfur atom, in particular indolyl, 2,3-dihydro-benzo- [1,4] -dioxinyl, benzo-furanyl, 4H-benzo- [1,4] -oxazin-3-onyl, benzooxazolyl, benzo- [1, 2,5] -oxadiazolyl, benzimidazolyl or benzothiophenyl, more preferably benzothiophenyl. When the heterocyclyl fraction is substituted, it is preferably mono-substituted. Suitable substituents for the heterocyclyl fraction are as defined herein, preferably -alkyl of 1 to 7 carbon atoms, such as methyl, halogen, hydroxyl, alkanoyl of 1 to 7 carbon atoms, such as acetyl, phenyl unsubstituted or substituted, preferably unsubstituted, unsubstituted or substituted phenyl- or naphthyl-oxyl, preferably unsubstituted, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, preferably unsubstituted, cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted, preferably unsubstituted carbon, such as cyclopropyl, nitro, amino, amino-alkyl of 1 to 7 carbon atoms, carboxyl, and cyano. More preferably, the heterocyclyl fraction is unsubstituted or is mono-substituted as described above, for example, by halogen. Alternatively, R3 and R4 can form a nitrogen-containing ring as described herein, preferably, R3 and R4 together form a pyrrolidine, imidazolidine or piperidine ring that is unsubstituted or substituted and can preferably contain a fraction oxo. When the ring is substituted, it is preferably substituted by up to four fractions selected from alkyl of 1 to 7 carbon atoms, hydroxyl, halogen, hydroxy-alkyl of 1 to 7 carbon atoms, halo-alkyl of 1 to 7 atoms of carbon and cyano. Preferably the ring is unsubstituted. The particular embodiments of the invention, in particular of The compounds of the formula I and / or the salts thereof are provided in the Examples - therefore, in a highly preferred embodiment, the invention relates to a compound of the formula I, or a salt thereof, selected from the compounds given in the Examples, as well as the use thereof according to the invention. Manufacturing process A compound of formula I, or a salt thereof, is prepared in a manner analogous to methods which, for other compounds, are in principle known in the art, such that, for novel compounds of the Formula I, the process is novel at least as an analogy process, especially as described or in analogy to the methods described herein in the Illustrative Examples, or modifications thereof, preferably in general by: a) for the manufacture of a compound of the formula I, wherein R1 is hydrogen, and R2, R3, R4 and T are as defined for a compound of the formula I hereinafter or hereinafter (preferably with the condition that R4 has one of the meanings given in the present different from N-mono- or N, N-di- (unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted alkyl) tuido) -aminocarbonyl), reacting a compound of the formula II: wherein R2, R3 and T are as defined for a compound of formula I, PX is R1 as defined for a compound of formula I, a protecting group or a linked resin, and PG is a protecting group, with a composed of the formula lll: R4-A (lll) wherein R 4 is as defined for a compound of formula I above or hereinbelow, and A is activated hydroxyl; or b) reacting a compound of formula IV: wherein T is methylene or preferably carbonyl, PG is a protecting group, and R3 and R4 are as defined for a compound of the formula I, or (preferably) an activated derivative thereof, with a compound of the formula V : R1-NH-R2 (V) wherein R1 and R2 are as defined for a compound of the formula I; or c) for the manufacture of a compound of the formula I, wherein R 1 is hydrogen, R 4 is N-mono- or N, N-di- (unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or alkyl) unsubstituted or substituted) -aminocarbonyl, and R 2, R 3 and T are as defined for a compound of formula I hereinafter or hereinafter, reacting a compound of formula II as given in a ) above, with a compound of formula VI: R4 * -NCO (VI) wherein R4 * is unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted alkyl; or d) for the manufacture of a compound of the formula I, wherein R 1 is hydrogen, R 4 is unsubstituted or substituted alkyl linked by means of a methylene group (which may be unsubstituted or substituted alkyl alkyl, or may be part of the same), and R2, R3 and T are as defined for a compound of formula I hereinabove or hereinafter, reacting a compound of formula II as given in a) above, with an oxo compound of the formula Vi l, R4 ** - C (= 0) R4 '(V i l) wherein R4 * * and R4 * * * with the bonding carbon atom are independently hydrogen or a fraction that completes an unsubstituted or substituted R4 alkyl moiety linked via the carbon atom bearing the oxo group (= 0) in the formula Vi l, under conditions of reductive amination; and, if desired, after any one or more of the processes mentioned above, converting a compound that can be obtained from the formula I or a protected form thereof into a different compound of the formula I, converting a salt of a compound that can be obtained from the formula I in the free compound or in a different salt, converting a free compound that can be obtained from the formula I into a salt thereof, and / or separating a mixture of isomers obtainable from a compound of the formula I in the individual isomers; wherein, in any of the starting materials (especially formulas II to VI), in addition to the specific protective groups mentioned, there may be other protective groups present, and any of the protective groups or linked resins are removed in an appropriate step in order to obtain a corresponding compound of the formula I, or a salt thereof.
Preferred reaction conditions The preferred reaction conditions for the reactions mentioned above, as well as for transformations and conversions, are as follows (or analogous to the methods employed in the Examples or as described therein): The reaction under a) , the reaction conditions and the reagents can be of the customary type, for example, they can preferably be as follows: the activated hydroxyl A in the formula III can preferably be halogen, such as chlorine, bromine or iodine, or in the case that R4 is a fraction as defined for R4 herein, other than acyl, the fraction of a sulfonic acid linked by means of an oxygen, such as toluene-sulphonyloxy or methanesulfonyloxy, or if R4 is an acyl fraction , the activated hydroxyl may be the fraction of an organic carbon or sulfonic acid (preferably alkanoyl of 1 to 7 carbon atoms, thereby forming a symmetric anhydride) oo mixed, or the acyl fraction of the same acid, thus forming a symmetrical anhydride) bound by oxygen, a fraction that completes an activated ester, such as hydroxybenzo-triazole (HOBT), pentafluoro-phenyl, 4-Nitro-phenyl or N-hydroxysuccinimide ester, or the activated hydroxyl can be formed in situ from the corresponding hydroxyl, for example, by contacting the compounds of the formulas II and III with a suitable solvent, for example a halogenated hydrocarbon, such as methylene chloride,?,? / - dimethyl-formamide,? /,? / - dimethyl-acetamide,? / - methyl-2-pyrrolidone, dimethyl-amino-pyridine, methylene chloride, or a mixture of two or more of these solvents, and by the addition of a suitable base, for example pyridine, triethylamine, di-isopropyl-ethyl-amine (DIEA) or / -methyl morpholine and, if the reactive derivative of the acid of the formula III is formed in situ, a suitable coupling agent which forms a preferred reactive derivative of the carbonic acid of the formula III in situ, for example dicyclohexyl-carbodiimide / 1-hydroxy-benzo-triazole (DCC / HOBT); bis- (2-oxo-3-oxazolidinyl) -phosphinic chloride (BOPCI); tetrafluoro-borate of 0- (1, 2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyl-uronium (TPTU); O-benzotriazole-1-i) tetrafluoroborate -N, N, N ', N' -tetramethyl-U-thio (TBTU); (benzotriazol-1-yloxy) -tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), 1- (3-dimethyl-amino-propyl) -3-ethyl-carbodi-imide / hydroxy-benzotriazole hydrochloride or / 1-hydroxy-7- aza-benzotriazole (EDC / HOBT or EDC / HOAt), HOAt alone, 4- (4,6-dimethoxy-1, 3,5-triazin-2-yl) -4-methyl-morpholinium chloride (DMT-MM) , propyl-phosphonic anhydride or with 1-chloro-2-methyl-propenyl) -dimethyl-amine (= 1-chloro-N, N, 2-tri-methy1-1-propenyl-amine). For a review of some other possible coupling agents, see for example, Klauser; Bodansky, Synthesis 1972, 453-463. Preferably, A in formula III is halogen, such as chlorine or bromine. The reaction mixture is preferably stirred at a temperature between about -20 ° C and 60 ° C, especially between 0 ° C and 50 ° C, for example, between room temperature and 40 ° C. The solvent is a customary solvent, for example a halogenated hydrocarbon, such as methylene chloride,? /,? / - dimethyl-formamide,? /,? / - dimethyl-acetamide,? / - methyl-2-pyrrolidone, dimethylaminopyridine, methylene chloride, or a mixing of two or more of these solvents, and preferably a suitable base is added, for example pyridine, triethyl-amine, di-isopropyl-ethyl-amine (DIEA) or N-methyl-morpholine. The reaction can be carried out under an inert gas, for example, nitrogen or argon. A PX protecting group may be selected from customary amino protecting groups, such as lower alkylcarbonyl or other such protecting groups, as can be deduced, for example, from the conventional textbooks mentioned below under the General Conditions of the Process. The removal of this protecting group after the reaction between a compound of the formula II and a compound of the formula III can take place under the customary conditions, for example, as it is described in conventional textbooks justly referenced. For example, the alkoxy of 1 to 7 carbon atoms, such as terbutoxycarbonyl, can be removed by reaction with an acid, such as hydrochloric acid, in an appropriate solvent, such as dioxane or methylene chloride, the temperatures customary, for example, in the range of 0 ° C to 50 ° C, for example at room temperature, or using CF3S03Si (CH3) 3 or the like, in an appropriate solvent, such as methylene chloride, in the presence of 2,6-lutidine, where temperatures can be in the same range as just It was described. When PX is a resin, it can include any resin that is appropriate and the bond with which the rest of the compound of the formula II or the resulting protected compound of the formula I can be reversed (i.e., the rest can be removed). of the molecule); Among the possible resins, polystyrene-based resins are particularly preferred where bonding is possible by means of appropriate linking groups, for example, -CH2-N (CH3) -C (= 0) - (CH2) 4 -0- (3,5-dimethoxy-phenyl) -4-methylene or -CH2-0- (CH2) 2-0- (3,5-dimethoxy-phenyl) -4-methylene, where the latter methylene is linked with the nitrogen in formula II, and the CH2 on the left is bonded with the resin matrix, such as polystyrene. The removal of the PX fraction can then take place in the presence of an acid, such as a strong organic acid, for example trifluoroacetic acid, at appropriate temperatures, for example, from 0 ° C to 50 ° C, such as at room temperature. Before, or after, or simultaneously with, the removal of a protective group or PX resin, the protecting group PG (and, if present, other protecting groups) can be removed under appropriate conditions, for example, selected from those mentioned in the conventional textbooks given under the General Conditions of the Process. For example, a protecting group of 9H-fluoren-9-yl-methyloxycarbonyl can be removed by reaction with an appropriate secondary nitrogen base, such as piperidine, in an appropriate solvent, such as an N, N-di- (alkyl of 1 to 7 carbon atoms) -C? -C7-alkanoylamide, for example, dimethyl acetamide, at the customary temperatures, for example, from 0 ° C to 50 ° C , for example at room temperature; C 1 -C 7 alkoxycarbonyl, such as terbutoxycarbonyl, can be removed by reaction with an acid, such as hydrochloric acid, in a suitable solvent, such as dioxane or methylene chloride, at the customary temperatures, for example, in the range of 0 ° C to 50 ° C, for example at room temperature, or using CF3S03Si (CH3) 3 or the like, in an appropriate solvent, such as methylene chloride, in the presence of 2,6- lutidine, where the temperatures can be in the same interval as just described. The removal of the protecting groups including PG and a protecting group PX or a PX resin consequently leads to a compound of the formula I, or a salt thereof. The reaction under b) preferably takes place under the customary conditions of condensation or substitution. In the case of a compound of formula IV wherein T is carbonyl (ie, the compound of formula IV is a carbonic acid), the reaction preferably takes place with an activated derivative of the compound of formula IV. As an activated derivative of an acid of formula IV, reactive esters (such as hydroxy-benzo-triazole (HOBT), pentafluoro-phenyl, 4-nitro-phenyl or N-hydroxy-succinimide ester), halides are preferred. of acid (such as acid chloride or bromide), or reactive anhydrides (such as mixed anhydrides with lower alkanoic acids or symmetrical anhydrides). Reactive carbonic acid derivatives can also be formed, and preferably formed, in situ. The reaction is carried out by dissolving the compounds of formulas IV and V in a suitable solvent, for example a halogenated hydrocarbon, such as methylene chloride,? /,? / - dimethylformamide,? /,? / -dimethyl-acetamide,? / -methyl-2-pyrrolidone, methylene chloride, acetonitrile, or a mixture of two or more of these solvents, and by the addition of a suitable base, for example triethyl-amine, di-isopropyl- ethyl-amine (DIPEA), or? / -methylmorpholine and, if the reactive derivative of the acid of the formula IV is formed in situ, a suitable coupling agent which forms a preferred reactive derivative of the carbonic acid of the formula IV in in situ, for example dicyclohexyl-carbodi-im ida / 1-hydroxy-benzo-triazole (DCC / HOBT); bis- (2-oxo-3-oxazolidinyl) -phosphinic chloride (BOPCI); 0- (1, 2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyl-uronium tetrafluoroborate (TPTU); O-benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium tetrafluoroborate (TBTU); (benzotriazol-1-yloxy) -tripyrrolidino-phosphonium hexafluoro-phosphate (PyBOP), 1- (3-dimethyl-amino-propyl) -3-ethyl-carbodi-imide / hydroxy-benzotriazole hydrochloride or / 1-hydroxy- 7-aza-benzotriazole (EDC / HOBT or EDC / HOAt), HOAt alone, 4- (4,6-di methoxy-1, 3,5-triazin-2-yl) -4-methyl-morpholinium chloride (DMT -MM), 0- (1 H -6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluorophosphate (HCTU), propyl-phosphonic anhydride or with 1-chloro-2- methyl-propenyl) - dimethylamine (= 1-chloro-N, N, 2-trimethyl-1-propenyl-amine). For a review of some other possible coupling agents, see for example, Klauser; Bodansky, Synhtesis 1972, 453-463. The reaction can take place at a temperature between about -20 ° C and 50 ° C, especially between 0 ° C and 30 ° C, for example, at 0 ° C at room temperature. The reaction can be carried out under an inert gas, for example, nitrogen or argon. In the case of a compound of formula IV wherein T is methylene, in an activated derivative, the OH group is preferably replaced by a leaving group, such as halogen, for example, chlorine, bromine or iodine, or organic sulfonyloxy, such as tosyloxyl or methanesulfonyloxy. The reaction with a compound of formula V then preferably takes place under conventional conditions for nucleophilic substitution. The removal of the protective groups PG and / or other protective groups can then take place in any case as described in process a) or in the General Conditions of the Process. The reaction under c) between a compound of the formula II and an isocyanate of the formula VI can take place under the customary reaction conditions known in the art for analogous reactions. For example, the reaction can take place in an appropriate solvent, such as 1,2-dichloroethane or methylene chloride, in the presence of a base, for example, a tertiary nitrogen base, such as pyridine, and, for example, at temperatures from 20 ° C to reflux temperature of the reaction mixture, for example, from room temperature to 80 ° C. The removal of the PX protecting groups, the PX resins, the PG protecting groups, and / or other protective groups can then take place in any case as described in process a) or in the General Process Conditions. The reaction under d) can take place in one step, or by first forming the corresponding quetimine or aldimine, which is then reduced to the amine of the formula I. In the first case, the reductive amination preferably takes place under the conditions customary for reductive amination, for example, in the presence of an appropriate hydrogenation agent, such as hydrogen in the presence of a catalyst or a complex hydride, for example, sodium triacetoxy-borohydride or sodium cyano-borohydride, in a suitable solvent, such as a halogenated hydrocarbon, for example, methylene chloride or 1,2-dichloroethane, and optionally a carbonic acid, eg, acetic acid, preferred temperatures between -1 0 ° C and 50 ° C, for example, from 0 ° C to room temperature. In the second case, the reaction takes place first (where, preferably, in formula II, PX is a resin) between a compound of formula II and the formula VI, up to a corresponding aldimine or quetimine, for example , in customary solvents, such as tri-lower alkyl ortho-formulations, such as trimethyl orthoformate, and / or halogenated hydrocarbons, such as methylene chloride, wherein temperatures may be, for example, in the range of 0 ° C to 50 ° C, for example, at room temperature; then, a resulting aldimine or quetimine intermediate, after isolation or without isolation (in the case of PX as a resin, for example, After washing the resin), it can be further reacted under reduction to a corresponding amine of the formula I, for example, in the presence of an appropriate hydrogenation substance, such as an appropriate complex hydride, for example, a borane-pyridine complex, for example in an appropriate solvent, for example, an alcohol, such as methanol, a halogenated hydrocarbon, such as methylene chloride, and a carbonic acid, such as acetic acid, or mixtures of two or more thereof, wherein the reaction temperatures may be, for example, in the range of 0 ° C to 50 ° C. ° C, for example, at room temperature. R4 ** and R4 ***, in a compound of the formula VII, with the bonding carbon atom, are independently hydrogen or a fraction that completes an unsubstituted or substituted alkyl fraction R4 linked via the carbon atom carrying the oxo group (= 0) in the formula VII, means that the fractions R4 ** and R4 ***, together with the carbon atom between them, during the reaction or the reactions, form an unsubstituted or substituted alkyl fraction R4 which is linked by means of the central carbon atom, which then carries R4 **, R4 *** and a hydrogen, and the bond that links it to the rest of the molecule [ie, R4 is a fraction of the formula R4 ** - CH (R4 ***) -]. This fraction is then methyl (each R 4 ** and R 4 *** = H) or other unsubstituted alkyl, or is substituted alkyl. The removal of the PX protecting groups, the PX resins, the PG protecting groups, and / or other protective groups can then take place in any case as described in process a) or in the General Process Conditions. Reactions and optional conversions The compounds of formula I, or the protected forms thereof, obtained directly according to any of the above procedures, or after introducing new protecting groups, which are also subsequently included as starting materials for the Conversions, even if not specifically mentioned, can be converted to compounds other than formula I according to known procedures, and where required, after the removal of the protecting groups. When R1 is hydrogen in a compound of the formula I, it can be converted into the corresponding compound wherein R1 has a different meaning of given hydrogen for the compounds of the formula I, by its reaction with a compound of the formula XVII: R1 * -Q (XVII) wherein R1 * is defined as R1 in a compound of formula I other than hydrogen, and Q is a leaving group (per example, preferably selected from halogen, for example chlorine, from unsubstituted or substituted arylsulfonyloxy, such as toluyl-sulfonyloxy, from unsubstituted or substituted alkylsulfonyloxy, such as methyl-sulfonyloxy or trifluoromethyl- sulfonyloxy, allowing the reaction to take place, for example, in the presence of a base, such as an alkali metal salt of a weaker acid, for example an alkali metal carbonate and / or an alkali metal acid carbonate, such as sodium or potassium carbonate and / or sodium or potassium hydrogen carbonate (NaHCO 3 or KHCO 3), in a suitable solvent, for example dimethyl acetamide, dioxane, and / or H 2 O, at preferred temperatures of between -20 ° C and 50 ° C. ° C, for example from -5 ° C to 30 ° C; or wherein Q is -CHO (such that the compound of formula IV is an aldehyde), and then R1 * is the complementary fraction for a fraction R1 that includes a methylene group (which results in a group R1 of the formula R1 * -CH2-), for example under conditions of reductive amination, as follows: The reaction preferably takes place under the conditions customary for reductive amination, for example in the presence of an appropriate hydrogenation agent, such as hydrogen, in the presence of a catalyst or a complex hydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent, such as a halogenated hydrocarbon, for example methylene chloride or 1,2-dichloroethane, and optionally a carbonic acid, for example acetic acid, at preferred temperatures of between -10 ° C and 50 ° C, example from 0 ° C to room temperature. In a compound of the formula I, wherein R3 is hydrogen, R3 can be introduced as unsubstituted or substituted alkyl by the reaction of a compound of the formula I wherein R3 is hydrogen, and R1, R2, R4, and T are as are defined for a compound of the formula I, with a compound of the formula XIX: R3-Q (XIX) wherein R3 is unsubstituted or substituted alkyl, and Q is as defined for a compound of formula XVII. Preferred reaction conditions are as described for the reaction of a compound of formula XVII in the previous paragraph. The reaction preferably takes place in the presence of a protecting group on the nitrogen atom of the central piperidine ring, that is, with a compound of the formula I in protected form, wherein R3 is hydrogen, which is subsequently removed. In some cases, the conversions preferably take place with the compounds of the formula I in protected form; the subsequent removal of the protecting group can be achieved as described above for the condensation reaction between a compound of the formula II and a compound of the formula III and below under the "General Process Conditions", producing a corresponding compound of the Formula I. The salts of the compounds of the formula I that they have when less a salt-forming group, can be prepared in a manner known per se. For example, salts of the compounds of the formula I having acid groups can be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of the suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with organic compounds of alkali metals or of alkaline earth metals, such as hydroxides, carbonates, or corresponding acidic carbonates, such as hydroxide, carbonate, or sodium or potassium hydrogen carbonate , with the corresponding calcium compounds, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt forming agent. The acid addition salts of the compounds of the formula I are obtained in the customary manner, for example by treating the compounds with an acid or an appropriate anion exchange reagent. The internal salts of the compounds of the formula I containing pharmacological groups of acidic and basic salts, for example a free carboxyl group and a free amino group, can be formed, for example, by the neutralization of the salts , such as the acid addition salts, up to the isoelectric point, for example with weak bases, or by their treatment with ion exchangers. A salt of a compound of formula I can be converted from the customary way in the book l ibre; the metal and ammonium salts can be converted, for example, by their treatment with suitable acids; and the acid addition salts, for example, by treatment with a suitable basic agent. In both cases, suitable ion exchangers can be used. Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se, by means of appropriate separation methods. For example, the diastereomeric mixtures can be separated into their individual diastereomers by means of fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds, or in a compound of the formula I itself. The enantiomers can be separated through the formation of diastereomeric salts, for example by the formation of salts with a pure qui ral acid in enantiomers, or by chromatography, for example by H PLC, using chromatographic substrates with ligands. what are you? The intermediates and the final products can be processed and / or purified according to conventional methods, for example using chromatographic methods, distribution methods, (re-) crystallization, and the like. Starting Materials In the following description of the starting materials (including this term also the intermediaries) and its synthesis, R1, R2, T, R1 *, R3, R4, R4 **, R4 ***, PG, PX, A, and Q have the meanings given above or in the Examples for the respective starting materials or intermediaries, if not otherwise indicated directly or by context. The protective groups, if not mentioned in a specific way, can be introduced and removed in the appropriate steps, in order to prevent functional groups, whose reaction is not desired in the step or corresponding reaction steps, using protective groups; the methods for their introduction and removal are described above or later, for example in the references mentioned under "General Process Conditions". The skilled person in this field will be able to easily decide if and which protective groups are useful or required. A compound of formula II, wherein PX is a bound resin, a protecting group, or R1 as defined for a compound of formula I, for example, can be prepared by the reaction of a compound of formula VIII: wherein R3 * is R3 or a protecting group, or a derivative reagent thereof, under condensing conditions, with a compound of formula IX: R2-NH-PX (IX) The reaction conditions for this condensation reaction, and the reactive derivatives of the carbonic acid of the formula VI II, can preferably be analogous to those mentioned in process b) above for the compounds of the formula IV, wherein T is carbonyl , and its reaction with a compound of the formula V. Then a corresponding compound of the formula II can be obtained, wherein T is methylene, by reduction of the compound obtainable of the formula II, wherein T is carbonyl. For example, this carbonyl can be reduced to a corresponding methylene by treatment with an appropriate complex hydride of the required specificity, especially a complex of borane-dimethyl sulfide, in an appropriate solvent, such as an ether, for example, tetrahydro -furan, at the preferred temperatures between the ambient temperature and the reflux temperature of the reaction mixture or from 1 40 ° C to 1 50 ° C. A subsequent removal of the protecting group R3 * can be achieved in a compound that can be obtained from the formula X: wherein R3 * is a protecting group, as above for reaction a) and below under the "General Process Conditions", providing a corresponding compound of formula I I, wherein R3 is hydrogen. For example, R3 * as terbutoxycarbonyl can be removed by reaction with CF3S03Si (CH3) 3 / 2,6-lutidine under conditions as mentioned above under manufacturing process a). When R3 * corresponds to a fraction R4 (such as terbutoxycarbonyl which is not to be removed), this compound which can be obtained from the formula I I, can already be a compound of the formula I.
A compound of the formula VI I I can be obtained, for example, from a corresponding salt, for example, an ammonium salt of the formula XI: wherein R3 * is as defined for a compound of the formula VI I I, by converting this salt under the introduction of a protective group PG into a protected compound corresponding to the formula VIII, for example, by introducing a protective group from an activated form of a carbonic acid forming the protective group PG, such as an activated form of "9-fluorenyl-methoxy-carbonic acid", for example, N- (9-fluorenyl-methoxy-carbonyloxy) -succinimide, in the presence of a base, for example, an alkali metal carbonate and / or acid carbonate, such as sodium carbonate, in an appropriate solvent, such such as water, tetrahydrofuran or mixtures of these solvents, for example, at temperatures in the range of 0 ° C to 50 ° C, for example at room temperature. For example, a salt compound of the formula XI can be obtained by reducing a nicotinic acid derivative of the formula Xll: in the presence of an appropriate reagent, for example, hydrogen, in the presence of an appropriate catalyst, such as rhodium oxide (III) / platinum (IV) oxide (Nishimura catalyst) in the presence of ammonium hydroxide and in an aqueous solvent, such as water, for example, at temperatures of 0 ° C to 50 ° C, for example at room temperature. A compound of formula IX, wherein PX is a fraction PX * -CH2 (ie, a PX moiety in the form of a resin, a protecting group, or of R1 as defined for a compound of the formula I, in each case comprising and linked via a methylene group) by example, it can be prepared by the reaction of a compound of the formula Xl ll: PX * -CHO (Xlll) wherein PX * is a residue that completes a PX fraction of the formula PX * -CH2 as justly defined, under conditions of reductive amination, with a compound of the formula XIV: R2-NH2 (XIV) wherein R2 is as defined for a compound of the formula I; the preferred reaction may take place under the customary conditions for reductive amination, for example, under the formation of aldimine and its direct reduction in the presence of a suitable hydrogenation agent, such as hydrogen, in the presence of a catalyst or a complex hydride, for example, sodium triacetoxy-borohydride or sodium cyano-borohydride, in a suitable solvent, such as a halogenated hydrocarbon, for example, methylene chloride or 1,2-dichloroethane, and optionally a carbonic acid, example, acetic acid, at preferred temperatures between -1 0 ° C and 50 ° C, for example, from 0 ° C to room temperature, or first under the formation of aldimine, and then (with or without isolation of aldimine) its reduction to the amine of formula IX in a separate step - in this second case, first reaction (wherein, preferably in the formula Xlll, PX * is a resin) between a compound of the formula Xlll and the formula XIV until the corresponding aldimine takes place, for example, in customary solvents, such as tri-ortho-formates lower alkyl, such as trimethyl orthoformate, and / or halogenated hydrocarbons, such as methylene chloride, wherein the temperatures may be, for example, in the range of 0 ° C to 80 ° C, for example, from the temperature environment up to 60 ° C, and then, a resulting aldimine intermediate, after isolation or without isolation (in the case of PX * as a resin, for example, after washing the resin), it can be further reacted under reduction up to an amine corresponding to the formula IX, for example, in the presence of an appropriate hydrogenating substance, such as an appropriate complex hydride, for example, a borane-pyridine complex, for example in an appropriate solvent, for example, an alcohol, such as methanol, a halogenated hydrocarbon, such as methylene chloride, and a carbonic acid, such as acetic acid, or mixtures of two or more thereof, wherein the reaction temperatures may be, for example, in the range of 0 ° C at 50 ° C, for example, at room temperature. Some examples for the compounds of the formula Xlll and its Manufacturing are provided in the Examples given below, especially also versions where PX is a resin. Other comparable compounds of the formula X1 can be prepared in a manner analogous to those described in the Examples. A compound of formula IV, wherein T is carbonyl, for example, can be prepared by removal, from a compound of formula VI II as described above wherein R 3 * is a protective group, of the protecting group, for example, under the conditions described in process a) above, or in the General Process Conditions, for example terbutoxycarbonyl in the presence of an acid, such as hydrochloric acid, in an appropriate solvent, for example, dioxane, a temperatures, for example, from 0 ° C to 50 ° C, for example at room temperature. If R3 * in a compound of formula VI I is a R3 moiety as defined under formula I, this removal of a protecting group is not required. A compound of the formula IV, wherein T is methylene, can be prepared from a compound of the formula VII I, by reducing the carboxyl function in the presence of an appropriate complex hydride, for example, borane-sulfide of dimethyl, in a suitable solvent, for example, tetrahydrofuran, at the preferred temperatures of between -20 and 40 ° C, to obtain the corresponding hydroxymethylene compound. The reactions of the two preceding paragraphs result in a compound of formula XVI: which can then be reacted with a compound of formula III, as shown above in process a), under conditions comparable to those described for process a), to give the corresponding compound of formula IV. In a compound of formula IV, wherein R3 is hydrogen, hydrogen can be replaced by unsubstituted or substituted alkyl R3, as defined herein, by reaction with a compound of formula XVIII: R3-Q wherein R3 is unsubstituted or substituted alkyl, and Q is as defined for a compound of formula XVII above. The reaction conditions are preferably as described for the reaction of a compound of the formula XVII in the conversion of a compound of the formula I above. When, for any of the starting materials, there are isomers present (e.g., diastereomers, enantiomers), these can be separated according to the conventional procedures in the appropriate steps. Other starting materials, for example, the compounds of the formula III, V, VI, VII, XII or XVII, their synthesis or analogous methods for their synthesis, are known in the art, are commercially available available, and / or can be found in, or derived in an analogous manner from the Examples. General Process Conditions The following applies in general (where possible) to all the processes mentioned hereinafter and subsequently herein, while the reaction conditions specifically mentioned above or below are preferred: In any of the In the reactions mentioned hereinabove and hereinafter, protecting groups may be used where appropriate or desired, even when this is not mentioned in a specific manner, to protect functional groups that are not intended to take part in a given reaction, and can be introduced and / or removed at the appropriate or desired stages. Accordingly, reactions comprising the use of protecting groups are included as far as possible, provided that reactions are described without specifically mentioning the protection and / or deprotection in this specification. Within the scope of the disclosure, only an easily removable group that is not a constituent of the particular desired end product of formula I is designated as a "protecting group," unless the context otherwise dictates. The protection of the functional groups by such protective groups, the protective groups themselves, and the appropriate reactions for their introduction and removal, are described, example, in conventional reference works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley , New York 1999, in "The Peptides"; Volume 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th Edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosáuren, Peptide, Proteine" (Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derívate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (ie, without the presentation of unwanted side reactions), for example by solvolysis, reduction, photolysis, or alternatively under physiological conditions (for example, by enzymatic dissociation). All the aforementioned process steps can be carried out under the reaction conditions which are known per se, preferably those mentioned in a specific manner, in the absence, or, by custom, in the presence of solvents or diluents, of Preference is given to solvents or diluents that are inert towards the reagents used and that dissolve them, in absence or in the presence of catalysts, condensation or neutralization agents, for example ion exchangers, such as cation exchangers, for example in the H + form, depending on the nature of the reaction and / or the reactants, reduced, normal, or elevated temperature, for example in a temperature range from about -1 00 ° C to about 1 90 ° C, preferably from about -80 ° C to about 1 50 ° C, for example from -80 ° C C at -60 ° C, at room temperature, from -20 ° C to 40 ° C, or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and / or in an inert atmosphere, for example under an atmosphere of argon or nitrogen. Solvents from which those solvents that are suitable for any particular reaction can be selected include those mentioned in a specific manner, or, for example, water, esters, such as lower alkyl lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol, or 1-α 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, for example as methylene chloride or chloroform, acid amides, such as dimethyl formamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, example pyridine or N-methyl-pyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclo-hexane, hexane, or iso-pentane, or mixtures thereof, for example aqueous solutions, unless otherwise indicated another way in the description of the processes. These solvent mixtures can also be used in the processing, for example by chromatography or division. The invention also relates to the forms of the processes where a compound that can be obtained as an intermediate at any stage of the process is used as the starting material, and the remaining steps of the process are carried out, or where a starting material under the reaction conditions, or it is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound that can be obtained by the process according to the invention is produced. under the conditions of the process, and is further processed in situ. In the processes of the present invention, preference is given to using the starting materials which result in the compounds of the formula I described as being preferred. A special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples. The invention also relates to the novel starting compounds and intermediates described herein, especially those leading to the novel compounds of the formula I, or to the compounds of the formula I mentioned as being preferred in the present invention. the present. Pharmaceutical Use, Pharmaceutical Preparations, and Methods As described above, the compounds of the formula I are inhibitors of renin activity and, therefore, may be useful for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis followed by angioplasty, elevated intra-ocular pressure, glaucoma, abnormal vascular growth and / or hyperaldosteronism, and / or in addition, cognitive impairment, Alzheimer's disease, dementia, anxiety states and cognitive disorders, and the like. Hypertension is especially preferred, at least as a component of the disease to be treated, meaning that hypertension can be treated (prophylactically and / or therapeutically) alone or in combination with one or more additional diseases (especially those mentioned). The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the formula I, alone or in combination with one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions according to the present invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, for the purpose of inhibiting the activity of renin, and for the treatment of conditions associated with the activity of renin (especially inappropriate). These conditions include hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth, and / or hyperaldosteronism, and / or in addition, cognitive impairment, Alzheimer's disease, dementia, states of anxiety and cognitive disorders, and the like. Especially preferred is a disease comprising hypertension, more especially hypertension itself, wherein treatment with a pharmaceutical composition or the use of a compound of formula I for its synthesis is prophylactically and / or (preferably) therapeutically useful. Accordingly, the pharmacologically active compounds of the formula I can be used in the manufacture of pharmaceutical compositions comprising an effective amount thereof together or in admixture with excipients or vehicles. suitable for enteral or parenteral application. Preferred are gelatin capsules and tablets comprising the active ingredient together with: a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol; for tablets also, c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone; if desired, d) disintegrants, for example starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors, and sweeteners. The injectable compositions are preferably aqueous isotonic solutions or suspensions, and the suppositories are conveniently prepared from fat emulsions or suspensions. These compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain from about 0.1 to 75 percent by weight. percent, preferably from about 1 to 50 percent of the active ingredient. Formulations suitable for transdermal application include a therapeutically effective amount of a compound of the invention with a carrier. Convenient carriers include pharmacologically acceptable absorbable solvents to aid passage through the skin of the host. Characteristically, the transdermal devices are in the form of a patch comprising a backup member, a reservoir containing the compound optionally with carriers, optionally a speed control barrier to deliver the compound to the skin of the host at a time. speed controlled and previously determined for a prolonged period of time, and means to secure the device to the skin. In accordance with the above, the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by renin activity, preferably hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy post-infarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy, and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, elevated intra-ocular pressure glaucoma abnormal vascular growth, and / or hyperaldosteronism, and / or cognitive deterioration, Alzheimer's disease, dementia, anxiety states and cognitive disorders, as well as methods for their use. The pharmaceutical compositions may contain a therapeutically effective amount of a compound of the formula I, as defined herein, either alone or in a combination with another therapeutic agent, for example each in an effective therapeutic dose as reported in matter. These therapeutic agents include: a) antidiabetic agents, such as insulin, insulin derivatives, and mimetics; insulin secretagogues, such as the sulfonyl-ureas, for example Glipizide, glyburide, and Amaril; insulinotropic sulfonyl urea receptor ligands, such as meglitinides, for example nateglinide and repaglinide; ligands of the peroxisome proliferator-activated receptor (PPAR); inhibitors of protein tyrosine-1B phosphatase (PTP-1B), such as PTP-112; inhibitors of GSK3 (glycogen synthase kinase-3), such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands, such as GW-0791 and AGN-194204; inhibitors of the sodium-dependent glucose co-transporter, such as T-1095; inhibitors of glycogen phosphorylase A, such as BAY R3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-1 type peptide), GLP-1 analogs, such as Exendin-4 and GLP-1 mimetics; and inhibitors of DPPIV (dipeptidyl peptidase IV), such as LAF-237; b) hypolipidemic agents, such as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) -reductase, for example lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin , rosuvastatin, and rivastatin; squalene synthase inhibitors; ligands FXR (farnesoid X receptor) and LXR (liver X receptor); cholestyramine; fibrates; nicotinic acid, and aspirin; c) anti-obesity agents, such as orlistat; and d) anti-hypertensive agents, for example cycle diuretics, such as ethacrynic acid, furosemide, and torsemide; angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril, and trandolapril; inhibitors of the Na-K-ATPase membrane pump, such as digoxin; Neutralendopeptidase (NEP) inhibitors; ACE / NEP inhibitors, such as omapatrilate, sampatrilate, and fasidotril; angiotensin II antagonists, such as candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan, in particular valsartan; ß-adrenergic receptor blockers, such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propanolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine, and milrinone; calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil; Aldosterone receptor antagonists; and inhibitors of aldosterone synthase. Other specific anti-diabetic compounds are described by Patel Mona in Expert Opin. Invest. Drugs, 2003, 12 (4), 623-633, in Figures 1 to 7, which are incorporated herein by reference. A compound of formula I can be administered either simultaneously, before, or after the other active ingredient, either separately by the same route of administration or by a different one, or together in the same pharmaceutical formulation. The structure of the therapeutic agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the databases, for example Patents International (for example, I MS World Publications). The corresponding content thereof is incorporated herein by reference. In accordance with the foregoing, the present invention provides pharmaceutical products or compositions comprising a therapeutically effective amount of a compound of the formula I, alone or in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from anti- diabetics, hypolipidemic agents, anti-obesity agents, and anti-hypertensive agents, more preferably from anti-diabetics, anti-hypertensive agents, and hypolipidemic agents, as described above. 18 The present invention further relates to pharmaceutical compositions as described above, for use as a medicament. The present invention further relates to the use of pharmaceutical compositions or combinations as described above, for the preparation of a medicament for the treatment of conditions mediated by an (especially inappropriate) activity of renin, preferably hypertension, atherosclerosis, unstable coronary syndrome , congestive heart failure, cardiac hypertrophy, cardiac fibrosis, post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy, and neuropathy, diseases of the coronary vessels , restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth, and / or hyperaldosteronism, and / or in addition, cognitive impairment, Alzheimer's disease, dementia, anxiety states, and cognitive disorders, and the like. Accordingly, the present invention also relates to a compound of the formula I, for use as a medicament; to the use of a compound of formula I, for the preparation of a pharmaceutical composition for the prevention and / or treatment of conditions mediated by an (especially inappropriate) activity of renin, and a pharmaceutical composition for use in 19 conditions mediated by an activity (especially inappropriate) of the renin, which comprises a compound of the formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier material. The present invention further provides a method for the prevention and / or treatment of conditions mediated by an (especially inappropriate) activity of renin, which comprises administering a therapeutically effective amount of a compound of formula I to a warm-blooded animal. , especially a human being, who needs such treatment. A unit dosage for a mammal of about 50 to 70 kilograms may contain between about 1 milligram and 1,000 milligrams, conveniently between about 5 and 600 milligrams of the active ingredient. The therapeutically effective dosage of the active compound depends on the species of warm-blooded animal (especially a mammal, more especially a human), the body weight, the age, and the individual condition, the method of administration, and of the compound involved. In accordance with the above, the present invention also provides a pharmaceutical product comprising a therapeutic combination, for example a kit, a kit of parts, for example for use in any method defined herein, which comprises a compound of the formula I, or a pharmaceutically acceptable salt of! same, to be used in a concomitantly or in sequence with at least one pharmaceutical composition comprising at least one other therapeutic agent, preferably selected from antidiabetic agents, hypolipidemic agents, anti-obesity agents, or anti-hypertensive agents. The kit may comprise instructions for its administration. In a similar manner, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition comprising a compound of the formula I according to the invention; and (ii) a pharmaceutical composition comprising a compound selected from an anti-diabetic, a hypolipidemic agent, an anti-obesity agent, an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of components (i) to (ii). In the same way, the present invention provides a method as defined above, which comprises the co-administration, for example concomitantly or in sequence, of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and at least one second drug substance, this second drug substance being preferably an antidiabetic, a hypolipidemic agent, an anti-obesity agent, or an anti-hypertensive agent, for example as indicated above. Preferably, a compound of the invention is administered to a mammal that needs it. Preferably, a compound of the invention is used for the treatment of a disease that responds to the modulation of the (especially inappropriate) activity of renin, especially one or more of the specific diseases mentioned above. Finally, the present invention provides a method or use, which comprises administering a compound of formula I, in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent, or an anti-obesity agent. the hypertension. Finally, the present invention provides a method or use, which comprises administering a compound of formula I, in the form of a pharmaceutical composition as described herein. The aforementioned properties can be demonstrated in in vitro and in vivo tests, conveniently using mamphers, for example mice, rats, rabbits, dogs, monkeys, or isolated organs, tissues and preparations thereof. These compounds can be applied in vitro in the form of solutions, for example preferably aqueous solutions, and in vivo, either enterally, parenterally, in a conveniently intravenous manner, for example as a suspension or in an aqueous solution. The level of concentration in vitro can be in the range of concentrations between approximately 10"3 molar and 10" 10 molar.
Therapeutically effective in vivo may be in the range, depending on the route of administration, of between about 0.001 and 500 milligrams / kilogram, preferably between about 0.1 and 1 00 milligrams / kilogram. As described above, the compounds of the present invention have enzyme inhibiting properties. In particular, they inhibit the action of the natural renin enzyme. Renin passes from the kidneys into the blood, where it dissociates angiotensinogen, releasing the decapeptide of angiotensin I, which then dissociates in the lungs, kidneys, and other organs, to form the octapeptide of angiotensin I I. The octapeptide increases blood pressure both directly by arterial vasoconstriction, and indirectly by the release from the adrenal glands of the sodium ion retention hormone, aldosterone, accompanied by an increase in the volume of extracellular fluid, the increase of which can be attributed to to the action of angiotensin II. Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently, a smaller amount of angiotensin I I is produced. The reduced concentration of this active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors. The action of renin inhibitors can be demonstrated, among other things, experimentally, by means of in vitro tests, measuring the reduction in the formation of angiotensin I in different systems (human plasma, purified human renin together with synthetic or natural renin substrate). The following in vitro tests may be used: Recombinant human renin (expressed in Chinese Hamster Ovary cells, and purified using conventional methods) is incubated in a concentration of 7.5 nM, with the test compound in different concentrations for 1 hour at room temperature, in 0.1 M Tris-HCl buffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA, and 0.05 percent CHAPS. The synthetic peptide substrate Arg-Glu (EDANS) -lle-His-Pro-Phe-His-Leu-Val-lle_His_Thr-Lys (DABCYL) -Arg9 is added to a final concentration of 2 μM, and the increase in fluorescence at an excitation wavelength of 350 nanometers, and at an emission wavelength of 500 nanometers, in a microplate-spectrum fluorometer. The IC50 values are calculated from the percent inhibition of renin activity as a function of the concentration of the test compound (Fluorescence Resonance Energy Transfer, FRET, assay). The compounds of the formula I, in this test, can preferably show IC 50 values in the range of 1 nM to 20 μM. In an alternative manner, recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using conventional methods) in a concentration of 0.5 nM, incubated with the test compound in different concentrations for 2 hours at 37 ° C, in 0.1 M Tris-HCl buffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA, and 0.05 percent CHAPS. The synthetic peptide substrate Arg-Glu (EDANS) -lle-His-Pro-Phe-His-Leu-Val-lle_His_Thr-Lys (DABCYL) -Arg9 is added to a final concentration of 4 μM, and the increase in fluorescence at an excitation wavelength of 340 nanometers, and at an emission wavelength of 485 nanometers, in a microplate-spectrum fluorometer. The IC5o values are calculated on the basis of the percentage inhibition of renin activity as a function of the concentration of the test compound (Fluorescence Resonance Energy Transfer, FRET, assay). The compounds of the formula I, in this test, can preferably show IC 50 values in the range of 1 n M to 20 μM. In another assay, human plasma spiked with recombinant human renin (expressed in Chinese Hamster Ovary cells is incubated, and purified using conventional methods) at a concentration of 0.8 nM, with the test compound in different concentrations for 2 hours at 37 ° C, in Tris / HCl 0.1 M, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA, and CHAPS at 0.025 percent (weight / volume). The synthetic peptide substrate Ac-lle-His-Pro-Phe-His-Leu-Val-I le-His-Asn-Lys- [DY-505-X5] is added to a final concentration of 2.5 μM. The enzymatic reaction is stopped by the addition of an excess of a blocking inhibitor. He The reaction product is separated by capillary electrophoresis, and quantified by spectrophotometric measurement at a wavelength of 505 nanometers. The IC50 values are calculated from the percentage inhibition of renin activity as a function of the concentration of the test compound. The compounds of the formula I, in this test, can preferably show IC 50 values in the range of 1 nM to 20 μM. In another assay, recombinant human renin (expressed in Chinese Hamster Ovary cells, and purified using conventional methods) is incubated at a concentration of 0.8 nM, with the test compound in different concentrations for 2 hours at 37 ° C, in 0.1 M Tris / HCl, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA, and 0.025 percent (weight / volume) CHAPS. The synthetic peptide substrate Ac-lle-His-Pro-Phe-His-Leu-Val-lle-His-Asn-Lys- [DY-505-X5] is added to a final concentration of 2.5 μM. The enzymatic reaction is stopped by the addition of an excess of a blocking inhibitor. The product of the reaction is separated by capillary electrophoresis, and quantified by spectrophotometric measurement at a wavelength of 505 nanometers. The IC50 values are calculated from the percentage inhibition of renin activity as a function of the concentration of the test compound. The compounds of the formula I, in this test, preferably show IC 50 values in the range of 1 nM to 20 μM. In animals deficient in salt, renin inhibitors cause a reduction in blood pressure. Human renin may differ from the renin of other species. In order to test inhibitors of human renin, primates, for example marmosets (Callithrix jacchus), may be used, because human renin and primate renin are substantially homologous in the enzymatically active region. Among others, the following in vivo tests can be used: The compounds of formula I can be tested in vivo in primates, as described in the literature (see, for example, Schnell CR et al., Measurement of blood pressure and heart rate by telemetry in conscious, unrestrained marmosets, Am. J. Physiol. 264 (Heart Circ. Physiol. 33). 1993: 1509-1516; or Schnell C. R. et al., Measurement of blood pressure, heart rate, body temperature, ECG and activity by telemetry in conscious, unrestrained marmosets. Memories of the fifth FELASA symposium: Welfare and Science. Eds. BRIGHTON. 1993. The following Examples, although in addition represent preferred embodiments of the invention, serve to illustrate the invention without limiting its scope. EXAMPLES The following examples serve to illustrate the invention without limiting its scope: Boc Terbutoxy-carbonyl abbreviations. (Boc) 20 Diterbutyl dicarbonate.
Celite Celite® is a filtration aid based on diatomaceous earth (registered trademark of Celite Corporation). DIPEA N-ethyl-di-isopropyl-amine. DMA N, N-dimethyl-acetamida. DMAP 4- (N, N-dimethylamino) -pyridine. DMF N, N-dimethyl-formamide. Fmoc 9-fluorenyl-methoxy-carbonyl. h Time (s). HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate. HCTU 0- (1 H -6-chlorobenzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluorophosphate. HM-N solute Sorbent of solute from International Sorbent Technology Ltd. mL Milliliters. MS Mass spectrometry. PS Polystyrene resin. RT Ambient temperature. TFA Trifluoroacetic acid. THF Tetrahydrofuran. Tosyl Para-toluene-sulfonyl. tR Retention time. Temperatures are measured in degrees Celsius. Unless indicated otherwise, reactions take place at temperature ambient. TLC conditions: Rf values for TLC are measured on plates of TLC 5 x 10 centimeters, silica gel F25, Merck, Darmstadt, Germany. Scheme 1 PS PS represents the polystyrene resin matrix, R2 can be as defined in the specification or examples.
Starting material 1: 5-terbu toxy-carbonyl-nama-1-piperidine-3-carboxylate. ammonium salt A mixture of 5-terbutoxy-carbonyl-amino-nicotinic acid (31.8 grams, 0.133 moles), Nishimura catalyst [Rh (lll) oxide / Pt (IV) hydrate] (6.37 grams) in distilled H20 (445) milliliters) and a 25 percent NH4OH solution (125 milliliters) is stirred at room temperature under H2 for 65 hours. After the addition of a second portion of catalyst (6.37 grams), stirring is continued for 25 hours. The reaction mixture is filtered through Celite and evaporated in vacuo to give the title compound as a white powder. MS: 245.1 [M + H] + Starting material 2: 1 - (9H-Fluoren-9-yl-methyl) -ester of the acid (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-d-carboxylic acid and 1 - (9H-fluoren-9-yl-methyl) -ester of the acid (3R * .5R * ) -5-terbutoxy-carbonyl-amino-piperidin-1,3-di-carboxylic acid To a stirred mixture of 5-terbutoxy-carbonyl-amino-1-piperidine-3-carboxylate, ammonium salt (31.76 grams, 0.122 moles), NaHCO3 (10.22 grams, 0.122 moles), distilled H2O (145 milliliters), and tetrahydro -furan (290 milliliters), N- (9-fluorenyl-methoxy-carbonyloxy) -succinimide (49.25 grams, 0.146 moles) is added in several portions. The reaction mixture is stirred for 22 hours at room temperature, and then the pH value is adjusted to 6 by the addition of 1M aqueous HCl. The mixture is diluted with H20 and extracted with ethyl acetate. The organic phase is washed twice with brine, dried (Na2SO4) and evaporated. Crystallization of the residue from ethyl acetate / hexane gives 1- (9H-fluoren-9-yl-methyl) -ester of (3S *, 5R *) - 5-terbutoxycarbonyl-amino-piperidin-1-ester , 3-dicarboxylic as a white powder. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + trifluoroacetic acid al 0. 1 percent / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 6.64 minutes. For Mass Spectrometry, a sample is treated with trifluoroacetic acid / CH2Cl2 for 10 minutes. MS: 367.0 [M + H-C5H802] + The filtrate consists of a mixture of approximately 1: 1 cis and trans isomers. Separation of the isomers by HPLC preparation (Nucleodur C18, 40-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 36 minutes) provides, in addition to the cis-isomer - (3S *, 5R *) previously described, also the trans isomer of the (3R *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin 1- (9H-fluoren-9-yl-methyl) -ester ester -1, 3-dicarboxylic acid as a white powder. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, 100 percent CH3CN + trifluoroacetic acid 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 6.58 minutes.
Starting Material 3A: 9H-Fluoren-9-yl-methyl-acid ester (3R *, 5S *) - 3-amino-5- (2.2-dif eni I -eti I -carbamoi I) -pipe ridi n-1 -carboxylic bound with polymer (Resin 1) The polystyrene resin of N-methyl-amino-methyl (263.5 grams, 540 mmol) is washed twice with dimethyl acetamide, and the solvent is drained. A mixture of 1-hydroxy-benzo-triazole (120.5 grams, 892 millimoles), 5- (4-formyl-3,5-dimethoxy-phenoxy) -pentanoic acid (229 grams, 811 millimoles), 1,3-diols isopropyl-carbodiimide (112.6 grams, 892 mmol), and dimethyl acetamide (1.85 liters) is stirred at room temperature for 30 minutes and then added to the wet resin together with the N-ethyl-di-isopropyl-amine ( 152.7 milliliters, 892 millimoles). The suspension is stirred for 2 hours at room temperature and for 16 hours at 50 ° C. The resin is filtered, washed with N, N-dimethyl-acetamide (2 times), H20 (2 times), NN-dimethyl-acetamide (1 time), tetrahydrofuran (2 times), CH2CI2 (4 times), CH3OH (2 times) and dried under high vacuum at 40 ° C. Part of the resulting resin (16.0 grams, 14.0 mmol) is washed twice with trimethyl orthoformate (150 milliliters, twice). To the wet resin is added 2,2-diphenylethylamine (12.6 grams, 64 millimoles) in trimethyl orthoformate (70 milliliters), and the The suspension is stirred for 20 hours at room temperature. The resin is filtered and washed with trimethyl orthoformate (2 times) and CH2Cl2 (4 times). To the wet resin is added a borane-pyridine complex solution (8 milliliters, 64 millimoles) in CH2Cl2 (70 milliliters), CH3OH (2.6 milliliters, 64 millimoles) and CH3COOH (3.66 milliliters, 64 millimoles), and the suspension it is stirred for 2 hours. The resin is filtered, washed with CH 2 Cl 2 (2 times); N, N-dimethyl acetamide (2 times); H20 (1 time); CH3OH (2 times); tetrahydrofuran (1 time); CH2Cl2 (2 times); CH3OH (2 times), and dried in vacuo. Part of the resulting resin (5 grams, 3.75 mmol) is swollen with N, N-dimethyl acetamide, and the solvent is drained. A mixture of (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) ester (3.5 grams, 7.5 mmol) , di-isopropyl-ethyl-amine (2.57 milliliters, 15 mmol) and 0- (7-azabenzotriazol-1-yl) -N, N, N *, N'-tetramethyl-uronium hexafluorophosphate (HATU) (2.85 grams, 7.5 mmol) in N, N-dimethyl acetamide (30 milliliters), is pre-activated for 20 minutes at room temperature by occasional stirring, and added to the wet resin. The suspension is stirred for 16 hours at room temperature, the resin is filtered, washed with N, N-dimethylacetamide (3 times), CH 3 OH (3 times) and CH 2 Cl 2 (4 times), and dried under vacuum at 50 ° C. . To a solution of CF3S03Si (CH3) 3 (9 milliliters, 49.8 millimoles) in CH2Cl2 (20 milliliters), a solution of 2,6-lutidine (8.6 milliliters, 73.8 millimoles) in CH2Cl2 (20 milliliters) is added. The mixture dilutes up to 100 milliliters with CH2Cl2. A 50 milliliter portion of this freshly prepared solution is added to the resin resulting from the last step above (6 grams, 3.36 millimoles), and the suspension is stirred for 30 minutes at room temperature. The liquid drains, the residue is treated with a second portion (50 milliliters) of the dissociation solution. After stirring for 30 minutes, the resin is filtered and washed with CH 2 Cl 2 (2 times), N, N-dimethyl-acetamide, CH 3 OH (3 times, alternating), and CH 2 Cl 2 (5 times), and dried under vacuum to provide the title compound. The N-methyl-amino-methyl polystyrene resin is prepared as follows: To the methyl-amine, maintained below -20 ° C, chloro-methyl-styrene copolymer (Merrifield resin) is added (approximately 1 gram of resin per 10 milliliters of methylamine). The suspension is stirred in a pressurized bottle at room temperature for 14 hours. The resin is filtered and washed with N, N-dimethyl acetamide (2 times), H20 (2 times), N, N-dimethylacetamide (1 time), CH3OH (2 times), CH2CI2 (3 times), CH3OH ( 2 times), and dried under a high vacuum.
Starting Material 3B: 9H-Fluoren-9-yl-methyl-acid ester (3R * .5S *) - 3-amino-5- (2,2-diphenyl-ethyl-carbamoyl) -pi-eridin-1-carboxylic acid and 9H-fluoren-9-yl-methyl-ester-acid (3R * .5R * ) -3-terbutoxy-carbonyl-amino-5- (2,2-diphenyl-ethyl-carbamoyl) -piperidine-1-carboxylic linked with polymer (Resin 2).
The title resin is prepared in a manner analogous to that described in Example 3A, using a 1: 1 mixture of 1- (9H-fluoren-9-yl-methyl) -ester of (3S *, 5R *) acid. -5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid and (3- (9H-fluoren-9-yl-methyl) -ester of (3R *, 5R *) - 5-terbutoxy-carbonyl-amino acid) -piperidin-1,3-dicarboxylic acid. Starting material 4: 9H-Fluoren-9-yl-methyl ester of (3R *, 5S *) - 3-amino-5-f (naphthalen-1-methyl-methyl) -carbamoyl-piperidin-1-carboxylic acid bound with polymer The title compound is prepared in a manner analogous to described in Example 3A, using 1-naphthalene-methyl-amine instead of 2,2-diphenylethylamine. Starting Material 5: 9H-Fluoren-9-yl-methyl-acid ester (3R * .5S *) - 3-amino-5- (2, 2-dif eni I -eti I -carbamoi I) -pipe ridi n-1 -carboxylic bound with polymer (Resin 3) The 2- (3,5-dimethoxy-4-formyl-phenoxy) ethoxy-methyl polystyrene (10.0 grams, 9 mmol) is washed twice with a solution of 30% trimethyl orthoformate in CH2Cl2 (150 milliliters, times). To the wet resin, a mixture of 2,2-diphenylethylamine (8.88 grams, 45 mmol) in a solution of 30% trimethyl orthoformate in CH2Cl2 (30 milliliters) is added, and the suspension is stirred for 14 hours at 60 ° C. The resin is filtered and washed with a 10 percent trimethyl orthoformate solution in CH2Cl2. To the wet resin is added a solution of borane-pyridine complex (4.55 milliliters, approximately 40 millimoles), CH3OH (1.83 milliliters, 45 mmol), and CH3COOH (2.57 milliliters, 45 mmol) in CH2Cl2 (40 milliliters), and the suspension is stirred for 2 hours. The resin is filtered, washed with N, N-dimethyl-acetamide, aqueous CH3COOH at 5 percent (2 times, alternating), H20 (2 times), tetrahydrofuran (2 times), aqueous NH4OH at 2 percent ( 2 times), CH3OH (2 times), tetrahydrofuran (2 times), CH2Cl2 (3 times); and it dries. The resulting resin (11 grams, 8.25 mmol) is swollen with N, N-dimethyl acetamide, and the solvent is drained. A mixture of (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-ylmethyl) ester (7.7 grams, 16.5 millimoles) , di-isopropyl-ethyl-amine (5.65 milliliters, 33 mmol), and 0- (1 H -6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluorophosphate (HCTU) (7.24 grams, 17.5 millimoles) in N, N-dimethyl acetamide (50 milliliters), is previously activated for 20 minutes at room temperature by occasional stirring, and added to the wet resin. The suspension is stirred for 18 hours at room temperature, the resin is filtered and washed with N, N-dimethyl acetamide. A second coupling is carried out using half the amount of acid, coupling reagent, and N-ethyl-di-isopropyl-amine. After 6 hours, the resin is filtered, washed with N, N-dimethyl acetamide (2 times), CH 3 OH, tetrahydrofuran (3 times, alternating), CH 2 Cl 2 (3 times), and dried. To a solution of CF3S? 3 Si (CH3) 3 (18.75 milliliters, 103.8 millimoles) in CH2Cl2 (50 milliliters), 2,6-lutidine (17.9 milliliters, 153.8 millimoles) is added. The mixture is diluted to 100 milliliters with CH2Cl2. A 50-milliliter serving of this solution prepared is added to the above resin (14.7 grams, 8.2 mmol), and the suspension is stirred for 30 minutes at room temperature. The liquid is drained, and the residue is treated with a second portion (50 milliliters) of the dissociation solution. After stirring for 30 minutes, the resin is filtered and washed with CH 2 Cl 2 (2 times), N, N-dimethyl acetamide, CH 3 OH (3 times, alternating) and CH 2 Cl 2 (5 times), and dried, to provide the composed of the title. Example 1: (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -pip.eridin-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate To resin 1 (starting material 3A) (3 grams, 1.77 millimoles), CH2Cl2 (15 milliliters), pyridine (3.55 milliliters, 44 millimoles), and 4- (N, N-dimethylamino) are added successively - pyridine (244 milligrams, 2 mmol), followed by a mixture of 4-toluene sulfonyl chloride (7.62 grams, 40 mmol) in CH2Cl2 (15 milliliters). The reaction mixture is stirred for 40 hours at room temperature. The resin obtained in this manner is filtered and washed with N, N-dimethyl-acetamide / H20, 1: 1 (3 times), CH 3 OH (3 times), tetrahydrofuran (2 times), CH 2 Cl 2 (4 times) . The Fmoc group is removed by stirring the resin wet for 15 minutes at room temperature, with a freshly prepared solution of N, N-dimethyl-acetamide / piperidine, 8: 2 (20 milliliters). After filtration, this procedure is repeated four times using fresh N, N-dimethyl-acetamide / piperidine solutions. The resin is filtered and washed successively with N, N-dimethyl acetamide and CH 3 OH (alternating, 2 times), then tetrahydrofuran (2 times), and then CH 2 Cl 2 (4 times). In order to dissociate the polymer compound, the obtained wet resin is stirred for 15 minutes with an 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (20 milliliters), and then filtered. This acid treatment is repeated twice using a fresh mixture of CH2Cl2 / 95 percent trifluoroacetic acid (20 milliliters) each time. The resulting acid solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (column C18 of 250 x 40 millimeters, 10-100 percent of CH3CN + trifluoroacetic acid at 0.1 percent / H20 + 0.1 percent / 30 minutes trifluoroacetic acid, flow : 60 milliliters / minute). The combined pure fractions are evaporated in vacuo to provide the title compound as a white solid. MS: 477.9 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.21 minutes.
The two enantiomers can be separated on a chiral column (Chiralpak AD-H). Example 2: (3R *, 5R *) - 5- (toluene-4-sulfonyl-amino) -pi eridin-3-carboxylic acid (2,2-diphenyl-ethy-D-amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 1, using resin 2 (starting material 3B) and 4-toluenesulfonyl chloride. After dissociation with CH2Cl2 / 95 percent trifluoroacetic acid (8: 2), the acidic solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (column C18 of 250 x 40 millimeters, 10-100 percent of CH3CN + trifluoroacetic acid at 0.1 percent / HzO + trifluoroacetic acid at 0.1 percent / 30 minutes, flow : 60 milliliters / minute). The combined pure fractions are evaporated in vacuo to provide the title compound (3R *, 5R *) and the corresponding (3S *, 5R *) isomer. MS: 477.9 [M + H] + * tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 5.33 minutes.
Example 3: (3S *. 5R *) - 5- (4-methoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate A suspension of resin 3 (starting material 5) (30 milligrams, 77 micromoles), CH2Cl2 (1.5 milliliters), pyridine (137 microliters, 1.7 millimoles), 4-dimethylaminopyridine (9.5 milligrams, 77 micromoles), and 4-methoxy-benzenesulfonyl chloride (320 milligrams, 1.55 millimoles), is stirred for 40 hours at 40 ° C. The resin is filtered, washed with N, N-dimethyl acetamide / H20, 1: 1 (3 times), CH3OH (3 times), tetrahydrofuran (2 times) and N, N-dimethylacetamide (4 times). The Fmoc group is stirred by stirring the wet resin for 15 minutes at room temperature, with a freshly prepared solution of N, N-dimethyl acetamide / piperidine 8: 2 (1 milliliter). After filtration, this procedure is repeated four times using fresh N, N-dimethyl-acetamide / piperidine solutions. The resin is filtered, washed successively with N, N-dimethyl acetamide and CH 3 OH (alternating, 2 times), then tetrahydrofuran (2 times), and then CH 2 Cl 2 (4 times). In order to dissociate the polymer compound, the wet resin is stirred for 15 minutes with an 8: 2 mixture of CH2Cl2 / trifluoroacetic acid at 95 percent (1 milliliter), and then it is filtered. This acid treatment is repeated once with a fresh mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter). The resulting acid solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute ). The combined pure fractions are evaporated in vacuo to provide the title compound. MS: 494.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.97 minutes. Example 4: (3S *, 5R *) - 5- (5-chloro-thiophene-2-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 5-chlorothiophen-2-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 504.4 [M + H] + tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.42 minutes. Example 5: (3S *, 5R * ') - 5- (quinoline-8-sulfonyl-amino) -piperdin-3-carboxylic acid (2, 3-phenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using quinoline-8-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 515.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.09 minutes.
Example 6: (3S *. 5R *) - 5-Phenyl-methanesulfonyl-amino-piperidine-3-carboxylic acid (2,2-diphenyl-ethy-D-amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using phenyl-methanesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 478.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.23 minutes. Example 7: (2,2-d-phenyl-ethyl) -amide of (3S *, 5R *) - 5- (4-chloro-benzene n-sulf or n-il-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 8, using 4-chloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 498.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.44 minutes. Example 8: (3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethn-amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3-chloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 498.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.43 minutes. Example 9: (3S *, 5R *) - 5- (2-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2-chloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 498.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.25 minutes. Example 10: (3S *, 5R *) - 5- (naphthalene-1-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 8, using 1-naphthalene sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 514.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.48 minutes. Example 11: (3S * .5R *) - 5- (4- (4-diphenyl-ethylamide methan-sulfonyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 4-methyl-sulfonyl-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 542.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.94 minutes. Example 12: (2,2-diphenyl-etl) -amide of (3S *, 5R *) - 5- (4-trifluoro-methoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to described in Example 3, using 4- (trifluoromethoxy) -benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 548.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.79 minutes. Example 13: (3S *, 5R *) - 5- (4-isopropyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethy-D-amide: trifluoroacetate) The title compound is prepared in a manner analogous to that described in Example 3, using 4-isopropyl-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 506.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.74 minutes. Example 14: (3S *, 5R *) - 5-methane (2,2-diphenyl-ethin-amide) sulphon-amino-piperidin-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using methan-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 402.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.56 minutes. Example 15: (3S *, 5R *) - 5- (2-acetylamino-4-methyl-thiazole-5-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2-acetamido-4-methyl-5-thiazole-sulfonyl chloride in place of 4-toluene-sulfonyl chloride. MS: 542.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.79 minutes. Example 16: (3S *. 5R *) - 5- (5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl-amino) (2,2-diphenyl-ethyl) -amide -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 2, using 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 516.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.94 minutes. Example 17: (3S *. 5R *) - 5- (2,4-difluoro-benzenesulfonyl-a) -piperidine-3-carboxylic acid, 2,2-diphenyl-ethylamide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,4-difluoro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 500.7 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.33 minutes. Example 18: (3S *, 5R *) - 5-r4- (2-oxo-propyl) -benzenesulfonyl-amino-1-piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 4- (2-oxo-propyl) -benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 520.0 / 521.0 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + acid 0.1 percent trifluoroacetic, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 5.07 minutes. Example 19: (3S *, 5R *) - 5- (4-cyano-benzenesulfonyl-amino) -piperidin-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 2, using 4-cyano-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 489.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.03 minutes. Example 20: (3S *, 5R *) - 5- (2,6-difluoro-benzenesulfonyl-amino) -p -peridin-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,6-difluoro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 500.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.02 minutes. Example 21: ((3S *, 5R *) - 5- (2-cyano-benzenesulfonyl-amino) -piperidine-3-carboxylic acid trifluoro-ethy-D-amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2-cyano-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 489.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.01 minutes. Example 22: (3S *, 5R *) - 5- (3-methoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3-methoxy-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 494.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.11 minutes. Example 23: (3S *, 5R *) - 5- (2-trifluoro-methyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2- (trifluoromethyl) -benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 5.37 minutes. Example 24: (3S *, 5R *) - 5- (4-acetyl-amino-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-etl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 4-acetamido-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 521.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.60 minutes. Example 25: (3S *, 5R *) - 5- (pyridine-3-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using pyridine-3-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 465.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.54 minutes. Example 26: (3S *, 5R *) - 5- (3-trifluoro-methyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethy-D) amide trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3- (trifluoromethyl) -benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.53 minutes. Example 27: (3S *. 5R *) - 5- (biphenyl-4-sulfonyl-amino) -piperidine-3-carboxylic acid (2, 3-diphenyl-ethylamide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using biphenyl-4-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 540.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.82 minutes. Example 28: (3S *, 5R *) - 5- (3-cyano-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3-cyano-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 489.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 5.20 minutes. Example 29: (3S *, 5R *) - 5- (3,4-dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3,4-dichloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.4 / 534.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.78 minutes. Example 30: (3S *. 5R *) - 5- (2,5-Dimethoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,5-dimethoxy-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 524.5 [M + H] + tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent of CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 5.25 minutes. Example 31: (3S *, 5R *) - 5- (4-phenoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 4-phenoxy-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 556.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.90 minutes. Example 32: (3S *, 5R *) - 5- (2,5-dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,5-dichloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.4 / 534.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.58 minutes. Example 33: (3S *, 5R *) - 5- (3,5-dichloro-benzenesulfonyl-amino) -pi eridin-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3,5-dichloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.4 / 534.2 [M + H] +; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + acid 0.1 percent trifluoroacetic / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute) : 5.76 minutes. Example 34: (3S *, 5R *) - 5-benzenesulfonyl-amino-piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 464.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2Q + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.16 minutes. Example 35: (3S *, 5R *) - 5- (2,4-dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,4-dichloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.4 / 534.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.65 minutes. Example 36: (3S *, 5R *) - 5- (Naphthalene-2-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-d-phenyl-ethyl) -amide. trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using naphthalene-2-sulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 514.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.59 minutes. Example 37: (3S *, 5R *) - 5- (2,3-) (2,2-diphenyl-ethyl) -amide dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2,3-dichloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 532.4 / 534.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.62 minutes. Example 38: (3S *, 5R *) - 5- (2-benzyloxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 2-benzyloxy-benzene chloride. sulfonyl (see International Publication Number WO 02/089749) in place of 4-toluene sulfonyl chloride. MS: 570.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.73 minutes. Example 39: (3S *, 5R *) - 5- (3-acetyl-benzenesulfonyl-1-amino) -pipe-1-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 3, using 3-acetyl-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride. MS: 506.2. [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.01 minutes.
Scheme 2 R4 * is a fraction that completes R4 * S02-, R4 * CO- or R4 * -CH2- with a fraction R4-PS represents the polystyrene resin matrix, R2 may be as defined in the specification or examples .
Example 40- (naphthalen-1-methyl-methyl) -amide of (3S *. 5R *) - 5-fBis- (3-chloro-benzyl) -amnol-piperid-3-carboxylic acid? co, trifluoroacetate Resin 1 (Starting Material 3A, 200 milligrams, 0.11 mmol) is washed twice with CH 2 Cl 2 and the solvent is drained. To the wet resin is added CH2Cl2 (2 milliliters), followed by 3-chloro-benzaldehyde (113 microliters, 1 millimole) and sodium triacetoxyborohydride (212 milligrams, 1 millimole). The suspension is stirred at room temperature for 20 hours. The resin is filtered, washed with N, N-dimethyl acetamide and H20 (alternating), then CH3OH, and then CH2Cl2, and then dried under vacuum. The resulting resin is swollen with N, N-dimethyl acetamide and the solvent is drained. A mixture of N, N-dimethylacetamide / piperidine 8: 2 (2 milliliters) is added to the wet resin, and the suspension is stirred for 10 minutes. After filtration, the resin is stirred with a fresh solution of N, N-dimethyl-acetamide / piperidine, 8: 2. This dissociation procedure is repeated 8 times. The resin is filtered and washed with N, N-dimethyl acetamide, CH 3 OH and CH 2 Cl 2. In order to dissociate the polymer compound, the wet resin is stirred for 20 minutes with an 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (3 milliliters), and then filtered. This treatment with acid is repeated using a fresh mixture of CH2Cl2 / 95 percent trifluoroacetic acid (3 milliliters). The two filtrates are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (19 x 50 C18 column, 20-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 30 minute trifluoroacetic acid, flow: 10 milliliters / minute). The combined pure fractions are evaporated in vacuo to provide the title compound. MS: 532.3 / 534.3 [M + H] +; tR (HPLC, Nucleosil C18, 40-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 3.69 minutes. Example 41: (3S *, 5R *) - 5- (4-methyl-benzoyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate To a suspension of resin 3 (starting material 5) (180 milligrams, 106 micromoles), CH2CI2 (1.5 milliliters), pyridine (188 microliters, 2.33 millimoles) and 4-dimethylaminopyridine (13 milligrams, 106 micromoles) , p-toluyl chloride (210 milligrams, 1.59 millimoles) is added, and the mixture is stirred for 40 hours at 40 ° C. The resin is filtered, washed with N, N-dimethyl acetamide / H20, 1: 1 (3 times), CH3OH (3 times), tetrahydrofuran (2 times) and N, N-dimethylacetamide (4 times). The Fmoc group is stirred by stirring the wet resin for 15 minutes at room temperature, with a freshly prepared solution of N.N-dimethyl acetamide / piperidine, 8: 2 (1 milliliter). After filtration, this procedure is repeated four times using fresh N, N-dimethyl-acetamide / piperidine solutions. The resin is filtered, washed successively with N, N-dimethyl acetamide and CH 3 OH (alternating, 2 times), then tetrahydrofuran (2 times), and then CH 2 Cl 2 (4 times). In order to dissociate the polymer compound, the wet resin is stirred for 15 minutes with an 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter) and then filtered. This acid treatment is repeated once with a fresh 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter). The resulting acid solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (column C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute). The combined pure fractions are evaporated in vacuo to provide the title compound. MS: 442.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.18 minutes. Example 42: (3S *, 5R *) - 5- (2-chloro-benzylamino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, trifluoroacetate To a suspension of the resin 3 (starting material 5) (180 μg, 106 micromoles) in a mixture of trimethyl orthoformate / CH 2 Cl 2 3: 7 (1.5 milliliters), 2-chloro-benzaldehyde (59.6 microliters, 0.53 mmol), and the mixture is stirred for 40 hours at 60 ° C. The resin is filtered, and then washed three times with trimethyl orthoformate / CH2Cl2 (1: 9). To the wet resin is added a mixture of borane-pyridine complex (53.5 microliters, approximately 0.45 mmol), CH 3 OH (21.5 microliters, 0.53 mmol), and CH 3 COOH (30.3 microliters, 0.53 mmol) in CH 2 Cl 2 (1.4 milliliters), and The suspension is stirred for 2 hours. The resin is filtered, washed with N, N-dimethyl-acetamide, 5% aqueous CH3COOH (2 times, alternating), H20 (2 times), tetrahydrofuran (2 times), 2 percent aqueous NH OH. (2 times), CH3OH (2 times), tetrahydrofuran (2 times) and N, N-dimethylacetamide (4 times). The Fmoc group is then stirred by stirring the wet resin for 15 minutes at room temperature, with a freshly prepared solution of N, N-dimethyl acetamide / piperidine 8: 2 (1 milliliter). After filtration, this procedure is repeated four times using fresh N, N-dimethyl-acetamide / piperidine solutions. The resin is filtered, washed successively with N, N-dimethyl acetamide and CH3OH (alternating, 2 times), then tetrahydrofuran (2 times), and then CH2CI2 (4 times). In order to dissociate the polymer compound, the wet resin is stirred for 15 minutes with an 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter) and then filtered. This acid treatment is repeated once with a fresh 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter). The resulting acid solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute ). The combined pure fractions are evaporated in vacuo to provide the title compound. MS: 448.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 4.47 minutes. Example 43: (3S *, 5R *) - 5- (3-Chloro-benzylamino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethy-D-amide) trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 42, using 3-chloro-benzaldehyde in place of 2-c, 1-chloro-benzaldehyde. MS: 448.4 [M + H] +; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 4.65 minutes. Example 44: .2.2-diphenyl-ethyl.-amide of (3S * .5R *) - 5-y3- (3-; loro-phenyl) -u re-idol-piperidin-3-carboxylic acid, trifluoroacetate To a suspension of resin 3 (starting material 5) (180 milligrams, 106 micromoles), 1,2-dichloroethane (1.5 milliliters) and pyridine (17 microliters, 0.21 millimoles), 3-chloro-phenyl isocyanate is added. (64.1 microliters, 0.53 mmol), and the mixture is stirred for 24 hours at 75 ° C. The resin is filtered, washed with CH2Cl2 (2 times), N, N-dimethyl acetamide / H20, 1: 1 (3 times), CH3OH (3 times), tetrahydrofuran (2 times), and N, N -dimethyl-acetamide (4 times). The Fmoc group is stirred by stirring the wet resin for 15 minutes at room temperature, with a fresh solution prepared from N, N-dimethyl-acetamide / piperidine 8: 2 (1 milliliter). After filtration, this procedure is repeated four times using fresh N solutions, N-dimethyl acetamide / piperidine. The resin is filtered, washed successively with N, N-dimethyl acetamide and CH 3 OH (alternating, 2 times), then tetrahydrofuran (2 times), and then CH 2 Cl 2 (4 times). In order to dissociate the polymer compound, the wet resin is stirred for 15 minutes with an 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter) and then filtered. This acid treatment is repeated once with a fresh 8: 2 mixture of CH2Cl2 / 95 percent trifluoroacetic acid (1 milliliter). The resulting acid solutions are combined and evaporated in vacuo. The crude product is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute ). The combined pure fractions are evaporated in vacuo to provide the title compound. MS: 477.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.41 minutes.
Scheme 3 R4 * is a fraction that completes R * 4S02- with a fraction R4 in formula I Example 45: (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (5,6-diethyl-indan-2-yl) -amide. trifluoroacetate To a frozen and stirred mixture of (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-1 - (9H-fluoren-9-yl-methyl) -ester ester dicarboxylic (190 milligrams, 0.365 millimoles) in pyridine (4 milliliters), 0- (1H-6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluoro-phosphate is added (166 milligrams, 0.40 millimoles). The mixture is stirred for 15 minutes at 0 ° C. After addition of 5,6-diethyl-indan-2-ylamine (82 milligrams, 0.365 millimole), stirring is continued for 5 hours at 0 ° C. The reaction is quenched by the addition of 2N HCl, and the acid mixture is extracted three times with tert-butyl methyl ether. The combined organic layers are washed with an aqueous solution of NaHCO 3 and brine, dried over Na 2 SO 4 and evaporated in vacuo to provide an amorphous solid. To a solution of this compound in CH2Cl2, piperidine (0.815 milliliters, 8.25 mmol) is added, and the mixture is stirred for 1 hour at room temperature. After evaporation under vacuum, the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute) to provide the title compound. MS: 470.5 [M-H] -; tR (HPLC, column C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 3.74 minutes. The starting materials are prepared as follows: A. 1- (9H-fluoren-9-yl-methyl) -ester (3S *, 5R *) - 5-amino acid piperidin-1,3-dicarboxylic acid, hydrochloride To a mixture of 1- (9H-fluoren-9-yl-methyl) -ester of (3S *, 5R *) - 5- te rbutoxycarbonyl-amino-piperidin-1 , 3-carboxylic acid (4.7 grams, 10.1 mmol) (see starting material 1 above) in dioxane (25 milliliters), add HCl (4M in dioxane, 25 milliliters, 100 mmol), and the reaction mixture Stir for 16 hours at room temperature. Hexane (50 milliliters) is added, and the crystals are filtered, washed with hexane and dried under vacuum to provide the title compound as a white solid. MS: 367.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.48 minutes. B. (3S *, 5R *) - 5- (toluene-4-sulphonyl-amino) -piperidine-1,3-dicarboxyl ester NaCl To a frozen and stirred mixture of the (3S *, 5R *) - 5-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) ester, hydrochloride (9.67 grams, 24 millimoles), K2C03 (4.98 grams, 36 millimoles in 50 milliliters of H20), KHC03 (3.6 grams, 36 millimoles in 36 milliliters of H20), and dioxane (85 milliliters), 4-toluene sulfonyl chloride ( 5.03 grams, 26.4 millimoles) in several portions, at a temperature of 0-5 ° C. Stirring is continued at this temperature for 1 hour. The reaction mixture is diluted with H20 and acidified with HCl to a pH of 2. The aqueous phase is extracted three times with ethyl acetate. After washing with brine, the combined organic extracts are dried (Na2SO4), and the solvent is evaporated in vacuo, to give the title compound as a white solid. MS: 521.1 [M-H] '; tR (HPLC, column C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 4.66 minutes. Example 46: (3R *, 5S *) - 5- (toluene-4-sulfonyl-amino) -piperi din -3-carboxylic acid (2-phenyl-2-pyridin-2-yl-ethyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 45, using 2-phenyl-2-pyridin-2-yl-ethyl-amine in place of 5,6-diethyl-indan-2-yl. -amine. MS: 479.5 [MH] "; tR (HPLC, column C18; 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 2.39 minutes Example 47: M- (4-chloro-phenyl) -cyclopropyl-methylamide of acid (3S * .5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 45, using C- [1- (4-chloro-phenyl) -cyclopropyl] -methyl-amine instead of 5,6-diethyl-indan -2-yl-amine, and a mixture of CH2Cl2 / CH3CN / N-ethyl-di-isopropyl-amine in place of pyridine for the coupling step. MS: 482.3 / 484.1 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.13 minutes. Example 48: r2- (4-methoxy-phenyl) -2-phenyl-ethyl-1-amide acid (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 45, using 2- (4-methoxy-phenyl) -2-phenyl-ethyl-amine in place of 5,6-diethyl-indan-2 -am-amine, and with purification by flash chromatography (CH2Cl2 / CH3OH). MS: 508.6 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 3.42 minutes. Example 49: (3S *. 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine- (2-f2- (4-methoxy-butoxy) -phenyl-2-phenyl-ethyl) -amide. 3-carboxylic An ice mixture of (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-ylmethyl) ester (208.2 milligrams, 0.4 mmol), 0- (1H-6-chloro-benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium hexafluoro-phosphate (182 milligrams, 0.44 mmol), and N-ethyl- di-isopropyl-amine (27.4 microliters, 0.16 mmol) in CH2Cl2 / CH3CN 1: 1 (3 milliliters), is stirred for 10 minutes. After the addition of 2- [2- (4-methoxy-butoxy) -phenyl] -2- phenyl-ethyl-amine (119.8 milligrams, 0.4 mmol), the ice bath is removed, and the stirring is continued for 14 hours at room temperature. The reaction mixture is distributed between ethyl acetate and a 10 percent K2C03 solution. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried over Na2SO4 and evaporated in vacuo. The residue is stirred for 1 hour with a fresh mixture of CH2Cl2 / piperidine 4: 1 (5 milliliters), evaporated, and the residue is purified by preparative HPLC (column C18, 10-100 percent CH3CN + trifluoric acid). - 0.1 percent acetic / H2O + 0.1 percent / 20 minutes trifluoroacetic acid, flow: 20 milliliters / minute). The combined pure fractions are treated with Na 2 CO 3, the CH 3 CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH 2 Cl 2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a light beige amorphous solid. MS: 580.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.61 minutes.
The starting material designated as 2- [2- (4-methoxy-butoxy) -phenyl] -2-phenyl-ethyl-amine is prepared as follows: a) A solution of [2- (3-methoxy-butoxy) - phenyl] -phenyl-acetonitrile (0.51 grams, 1.73 millimoles) in ethanol (7 milliliters) which it contains concentrated aqueous ammonia at 4 percent, it is hydrogenated in the presence of Raney Nickel (0.5 grams) for 6 hours at room temperature. The mixture is filtered over Celite, washed with ethanol, followed by evaporation of the combined filtrates, to give the title product. MS: 300.2 [M + H] +? tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 4.44 minutes. b) To a stirred solution of 1-benzyl-2- (3-methoxy-butoxy) -benzene (1.05 grams, 3.88 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.06 grams) , 4.66 mmol) in CH2Cl2 (10 milliliters), trt methyl-silicon cyanide (1.94 milliliters, 19.4 millimoles) was added, and the reaction mixture was heated at 100 ° C for 1 hour in a microwave reactor. After cooling to room temperature, the organics are washed with aqueous NaHC03 (10 percent) and water, dried (MgSO4) and concentrated. The product is purified by flash chromatography on silica gel (hexane / EtOAc, 97: 3 (0.5 liters), then hexane / EtOAc 85:15) to give [2- (3-methoxy-butoxy) -phenyl] phenyl acetonitrile. MS: 296.2 [M + H] +; tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 5.61 minutes. c) To a stirred solution of 2-benzyl-phenol (0.90 grams, 4.89 mmol) in acetonitrile (35 milliliters), add K2C03 without water (0.81 grams, 5.86 mmol), and 4-methoxy-butyl-acid ester. toluene-4-sulfonic acid (1.51 grams, 5.86 millimoles). The mixture is refluxed overnight, and filtered after cooling to room temperature, followed by evaporation. The residue is taken up in CH 2 Cl 2, and the organic phase is subsequently washed with 1 M NaOH (50 milliliters), water, and brine. The combined organics are dried (MgSO4) and evaporated. The residue is purified by flash chromatography on silica gel (hexane / EtOAC 93: 3) to give 1-benzyl-2- (3-methoxy-butoxy) -benzene. MS: 271.2 [M + H] + 'tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 6.25 minutes.
Scheme 4 Example 50: (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (biphenyl-2-methyl) -amide. trifluoroacetate A small part of the residue obtained below under A (40 milligrams, 0.1 millimoles), is dissolved in pyridine (0.5 milliliters). The solution is cooled to 2 ° C, treated with O- (1 H -6-chloro-benzotriazol-1-yl) -1,1,3-tetramethyl-uronium hexafluoro-phosphate and stirred at 2 ° C. C for 1 hour. The resulting mixture is added to a previously cooled solution of 2-phenyl-benzyl-amine (18.3 milligrams, 0.1 mmol) in pyridine (0.4 milliliters). The reaction mixture is stirred at 4 ° C for 14 hours, evaporated in a stream of air, and the residue is evaporated twice with CH 2 Cl 2. The crude product is dissolved in CH2Cl2 (2 milliliters), and placed on a 3 milliliter cartridge of HM-N (solute) previously treated with an aqueous solution of 10 percent K2C03 (2 milliliters). The compound is eluted with CH2Cl2 (6 milliliters, 2 times). The organic layer is evaporated and dried at room temperature. To the residue is added a solution of CH2Cl2 / trifluoroacetic acid (1: 1), the mixture is stirred for 1 hour at room temperature, and evaporated. The residue is purified by preparative HPLC (C18 column, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 30 milliliters / minute) to provide the title compound. MS: 464.2. [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 3.36 minutes. The starting material is prepared as follows: A. (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-1,3-dicarboxylic acid 1-terbutyl ester A mixture of the 1 - (9H-Fluoren-9-yl-methyl) -ester of the acid (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-1,3-dicarboxylic acid (11 grams, 21.1 mmol) (see Example 45 B.), piperidine (62.6 milliliters), 633 millimoles), and CH2Cl2 (170 milliliters), is stirred for 1 hour at room temperature. The solution is evaporated, and the residue is distributed between CH2CI2 and an aqueous solution of 10 percent KHC03. After separation, the aqueous layer is washed a second time with CH2Cl2. The combined organic layers are extracted with a 10 percent KHC03 solution. Total amount of KHC03 solution: 170 milliliters (10 percent solution). The combined aqueous solutions are treated with dioxane (170 milliliters) and diterbutyl dicarbonate (27.3 milliliters, 120 millimoles), and the resulting mixture is stirred for 16 hours at room temperature. After the addition of a K2C03 solution (10 percent, 50 milliliters), the mixture is washed twice with tert-butyl ether, and the aqueous layer is acidified slowly to a pH of 2 with a solutionote of NaHS04 at 10 percent. The aqueous layer is extracted three times with CH2Cl2. The combined organic layers are washed with H20, dried (Na2SO4), and evaporated, to give a residue. Example 51: r3- (4-methoxy-phenyl) -2-phenyl-propyl-amide acid (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 50, using 3- (4-methoxy-phenyl) -2-phenyl-propyl-amine in place of 2-phenyl-benzyl-amine. MS: 522.2 [M + H] +; tR (HPLC, C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 3.49 minutes.
Example 52: (2S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-3- (4-chloro-phenyl) -2-phenyl-etn-amide carboxylic The title compound is prepared in a manner analogous to that described in Example 45, using 2- (4-chloro-phenyl) -2-phenyl-ethyl-amine. MS: 512.1 / 514.1 [M + H] +; tR (HPLC, LiChrospher RP8 (Merck KGaA, Darmstadt, Germany); 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent percent CH3CN + 0.1 percent trifluoroacetic acid, for 2.5 minutes, flow: 1.5 milliliters / minute): 5.05 minutes. Example 53: Acid (2-phenyl-bicyclo-3,3.n-non-9-yl) -amide (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 50, using 2-phenyl-bicyclo- [3.3.1] -non-9-yl- amine instead of 2-phenyl-benzyl-amine. MS: 496.3 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.05 percent trifluoroacetic acid / H20 + 0.05 percent trifluoroacetic acid, for 6 minutes, flow: 1.5 milliliters / minute): 3.79 minutes.
Scheme 5 R4 * is a fraction that completes R4 * S02- with a fraction R4- as given in the formula Example 54: (3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2-chloro-benzyl) -cyclopropyl-amide To an ice-cold mixture of (3R *, 5S *) - 3-amino-5 - [(2-chloro-benzyl) -cyclopropyl-carbamoyl] -piperidine-9H-fluoren-9-yl-methyl ester 1 - . 1-carboxylic acid (209.3 milligrams, 0.37 millimoles) in pyridine (3 milliliters), 4-dimethylaminopyridine (12.7 milligrams, 0.104 millimoles) and 3-chloro-benzenesulfonyl chloride (210.5 microliters, 1.476 millimoles) are added. ). The reaction mixture is stirred at room temperature for 14 hours, then diluted with H20, and acidified with 1N HCl to a pH of 2, and the resulting aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO) and evaporated, to provide the Fmoc prted form or the title compound, as an amorphous white solid. To remove the prting group, the crude compound is stirred for 1 hour at room temperature, with a freshly prepared solution of CH 2 Cl 2 / piperidine, 4: 1 (5 milliliters). The reaction mixture is evaporated in vacuo, and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as an amorphous white solid. MS: 482.2 / 484.1 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 5.21 minutes. The starting materials are prepared as follows: A. 9H-Fluoren-9-yl-methyl-ester-acid (3R *, 5S *) - 3-terbutoxyl-carbon i-am i no-5 - [(2-chlorobenzyl) -cyclopropylcarbamic acid-1-carboxylic acid To an icy mixture and stirred from (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-di-carboxylic acid 1- (9H-fluoren-9-ylmethyl) ester (233.3 milligrams, 0.5 millimoles), (2-chloro-benzyl) -cyclopropyl-amine (99.9 milligrams, 0.55 millimoles), and N-ethyl-di-isopropyl-amine (685 microliters, 4 millimoles) in dimethyl acetamide (2.5 milliliters), add a solution of propyl-phosphonic anhydride (approximately 50 percent in N, N-dimethylformamide, 480 microliters, approximately 0.75 mmol). The reaction mixture is stirred for 14 hours at room temperature, diluted with ethyl acetate, and washed twice with an aqueous solution of NaHCO 3. The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoro- acid). acetic at 0.1 percent, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with Na 2 CO 3, the CH 3 CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH 2 Cl 2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as an amorphous white solid. MS: 630.7 [M + H] +; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 1.5 milliliters / minute): 8.24 minutes. B. (3R *, 5S *) - 3-amino-5-r (2-chloro-benzyl) -cyclopropyl-carbamoyl-piperidin-9H-fluoren-9-yl-methyl ester carboxylic acid A mixture of (3R *, 5S *) - 3-terbutoxy-carbonyl-amino-5 - [(2-chloro-benzyl) -cyclopropyl-carbamoyl] - 9H-fluoren-9-yl-methyl ester - piperidin-1-carboxylic acid (186 milligrams, 0.295 mmol) and HCl (5M in 2-propanol, 2 milliliters, 10 mmol), is stirred for 2 hours at room temperature. The mixture is evaporated, and the residue is dried, to provide the title compound as a beige amorphous solid. MS: 530.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.02 minutes. Example 55: Chloropropyl- (2,2-diphenyl-ethyl) -amide of] acid (3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic The title compound is prepared in a manner analogous to described in Example 54, using cyclopropyl- (2,2-diphenyl-ethyl) -amine in place of 2- (chloro-benzyl) -cyclopropyl-amine. MS: 538.3 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.72 minutes. Example 56: (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino-piperidine-3-carboxylic acid benzyl- (3-methyl-2-phenyl-butyl) -amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 54, using benzyl- (3-methyl-2-phenyl-butyl) -amine in place of 2- (chloro-benzyl) -cyclopropyl-amine . MS: 534.3 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.17 minutes. The starting material is prepared as follows: A. Benzyl- (3-methyl-2-phenyl-butyl-amine) The title compound is prepared from 3-methyl-2-phenyl-butyl-amine and benzaldehyde: a solution of 3-methyl-2-phenyl-butyl-amine (1.3 grams, 8 mmol) and benzaldehyde (0.81 milliliters) , 8 mmol) in CH2Cl2 (50 milliliters) is stirred at room temperature for 20 minutes. Sodium triacetoxy borohydride (2.52 grams, 11.3 millimoles) is then added, followed by acetic acid (0.46 milliliters, 8 millimoles). The reaction mixture is stirred at room temperature for 16 hours, and then quenched by the addition of a saturated solution of NaHCO 3. The organic layer is separated and the aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is purified by flash chromatography (hexane / ethyl acetate) to give benzyl- (3-methyl-2-phenyl-butyl) -amine as a colorless oil. MS: 254.3 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.03 minutes. Example 57: f2.2-b1s- (4S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxy (4-methoxy-phenylene-amide) Ilic The title compound is prepared in a manner analogous to that described in Example 45, using 2,2-b? S- (4-methox? -phen?) -et? -amma MS 5382 [M + H ] + tR (HPLC, Lichrospher RP8, 10-100 percent CH3CN + 01 percent tpfluoroacetic acid / H20 + 01 percent tpfluoroacetic acid, for 5 minutes, flow 5 milliliters / minute) 477 minutes Example 58 (2,2-d? Phen? L-et? L) -amide of (3S, 5R) -5- (toluene-4-sulfon? L-am? No) -p? Per? D acid ? n-3-carboxyl? co, tpf luoroacetate The title compound is prepared in a manner analogous to that described in Example 54, using 2,2-d? Phen? L-et? L-amine instead of 2- (chloro-benzyl) -c? clopropyl-amine and 1- (9H-fluoren-9-? l-met? l) -ester of (3S, 5R) -5-terbutox? -carbon? l-am? no. -p? per? d? n-1,3-dicarboxylic. MS-4783 [M + H] + tR (HPLC, column C18, 5-100 percent CH3CN + tolfluoroacetic acid at 005 per cacti / H2O + 005 percent tpfluoroacetic acid, for 6 minutes, flow 5 milliliters / minute) 534 minutes Scheme 6 * This compound is also a compound of the formula I Example 59: ((3R *, 5S *) - 5-rbenzyl- (3-methyl-2-phenyl-butyl) -carbamoyl-piperidin-3-ill-carbamic acid ester.
A solution of (3S *, 5R *) - 3- [benzyl- (3-methyl-2-phenyl-butyl) -carbamoyl] -5-terbutoxy-carbonyl-9H-fluoren-9-yl-methyl ester amino-piperidin-1-carboxylic acid (105.2 milligrams, 0.15 mmol) is stirred in a mixture of CH2Cl2 / piperidine, 4: 1 (5 milliliters) for 1.5 minutes. hours at room temperature. The reaction mixture is evaporated, and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes , flow: 20 milliliters / minute). The combined pure fractions are treated with K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as an amorphous white solid. MS: 480.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.05 minutes. The stag material is prepared as follows: A. (3S *, 5R *) - 3-fbenzyl- (3-methyl-2-phenyl-butyl) -carbamoyl-1H-fluoren-9-yl-methyl ester 5-terbutoxy-carbonyl-amino-piperidin-1-carboxylic acid To a frozen and stirred mixture of (3S *, 5R *) - 5-terbutoxy-carbonyl 1- (9H-fluoren-9-yl-methyl) -ester of (3S *, 5R *) acid -amino-piperidin-1,3-di-carboxylic acid (466.5 milligrams, 1 millimole), benzyl- (3-methyl-2-phenyl-butyl) -amine (279 milligrams, 1.1 millimole) and N-ethyl-di-isopropyl -amine (1.37 milliliters, 8 millimoles) in dimethyl acetamide (6 milliliters), a solution of propyl phosphonic anhydride (approximately 50 percent in N, N-dimethylformamide, 0.95 milliliters, approximately 1.5 millimoles) is added. . The reaction mixture is stir for 7 hours at room temperature, and evaporate in vacuo. The residue is dissolved in ethyl acetate, and washed twice with an aqueous solution of 10 percent K2CO3. The organic layer is dried (Na2SO4) and evaporated in vacuo, and the residue is purified by flash chromatography (hexane / ethyl acetate). The combined pure fractions are evaporated, to give the title compound as an amorphous white solid. MS: 702.3 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 1.5 milliliters / minute): 8.87 minutes. The amine used in Example 59 A is prepared as follows: B. Benzyl- (3-methyl-2-phenyl-butyl) -amine A mixture of 3-methyl-2-phenyl-butyl-amine (1.3 grams, millimoles), benzaldehyde (271 microliters, 2.66 mmol), and CH2Cl2 (50 milliliters), is stirred for 20 minutes at room temperature. NaBH (OAc) 3 (840 milligrams, 3.96 millimoles) and acetic acid (154 microliters, 2.69 millimoles) are added. After 2 hours, the same amounts as indicated above of behzaldehyde, NaBH (OAc) 3 and acetic acid are added once again. This procedure is repeated after 4 hours. After stirring for 16 hours at room temperature, a saturated solution of NaHCO 3 is added, the CH 2 Cl 2 layer is removed, and the aqueous phase is extracted twice with fresh CH 2 Cl 2. The organic layers The combined extracts are dried (Na2SO), evaporated in vacuo, and the residue is purified by flash chromatography (hexane / ethyl acetate). The combined pure fractions are evaporated, to give the title compound as a colorless oil. MS: 254.3 [M + H] + 'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.03 minutes. Example 60: Terbutil-acid ester ((3R * .5S *) - 5- (cyclopropyl-ri - (3-methoxy-propyl) -1H-indol-3-yl-methy-carbamoyl) -piperidin-3- il) -carbamic The title compound is prepared in a manner analogous to that described in Example 59, using cyclopropyl- [1- (3-methoxy-propyI) -1 H -indol-3-ylmethyl] -amine instead of benzyl- (3-methyl-2-phenyl-butyl) -amine. MS: 485.4 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.15 minutes. The starting material is prepared as follows: A. Cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methylamine The title compound is prepared as follows: A mixture of the indole-3-carboxaldehyde (4.18 grams, 28.8 mmol) and NaH (55-65 percent in oil, 1.38 grams, approximately 31 mmol) in dimethyl acetamide (60 milliliters), is stirred at 70 ° C for 30 minutes. After cooling to room temperature, 3-methoxy-propyl-ester of toluene-4-sulfonic acid (7.75 grams, 31.7 mmol) and potassium iodide (5.27 grams, 31.7 mmol) are added. The reaction mixture is stirred for 2 hours at 40 ° C, then evaporated in vacuo, and the residue is distributed between H20 and ethyl acetate. The organic layer is dried over Na2SO4 and evaporated. Flash chromatography of the residue (hexane / ethyl acetate) and evaporation of the pure fractions provide the 1-substituted indole as an orange oil. A mixture of this intermediate (1147 grams, 6.8 mmol), CH2Cl2 (50 milliliters), and cyclopropyl amine (1.6 milliliters, 22.8 mmol) is stirred for 20 minutes at room temperature. After the addition of sodium triacetoxyborohydride (2.14 grams, 9.6 mmol) and acetic acid (0.39 milliliters, 6.8 mmol), the reaction mixture is stirred for 16 hours at room temperature. The reaction is quenched by the addition of a saturated solution of NaHCO 3. The organic layer is separated, and the aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute) . The fractions Pure combined is treated with K2C03, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amine as a yellow oil. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.23 minutes. Starting Material 6: 9H-Fluoren-9-yl-methyl-acid ester (3R **, 5S *) - 3-amino-5-cyclopropyl-1 - (3-methoxy-prop i) -1 H-indol-3-yl-m eti II-carb a moi ll-p i pe ri di n-1 -carboxyl To a frozen and stirred solution of the (3R *, 5S *) - 3-terbutoxy-carbonyl-amino-5-9-fluoren-9-yl-methyl-ester ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidin-1-carboxylic acid (prepared from cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -amine, in a manner analogous to that described in Example 59A ) (1.2 grams, 1.7 mmol) in CH2CI2 (8 milliliters), 2,6-lutidine (0.79 milliliters, 6.8 millimoles) is added, followed by the trickle-trifluor-methane-sulfonate addition of tri-methyl-silyl (0.92). milliliters, 5.1 millimoles). The cooling bath is removed, and the The mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with CH2Cl2 and washed with a saturated solution of NH CI. The organic layer is dried over Na2SO4 and evaporated in vacuo to give the title compound as a brown solid, which is used without further purification for the following steps. MS: 607.5 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.05 minutes.
Scheme 7 R4 * is a fraction that completes R4 * NH-CO-, R4 * -O-CO- or R4 * -CO- for a fraction R4- as given in formula I Example 61: 2,2-dimethyl-propyl ester of ((3R *, 5S *) - 5-cyclopropyl-M - (3-methoxy-propyl) -1 H -i ndol-3-i I-methyl ester - carbamoi II-p i pe ridi n-3-i I) -carbamic To a mixture of the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidin-1-carboxylic acid (121.4 milligrams, 0.2 mmol) (starting material 6), N-ethyl-di-isopropyl-amine (171.2 microliters, 1 millimole), and 4-dimethyl-amino-pyridine (10 milligrams) in CH2CI2 (3 milliliters), neopentyl chloroformate (52.1 microliters, 0.35 mmol) is added. After stirring at room temperature for 14 hours, the mixture is diluted with CH2Cl2. The organic layer is washed with 1N HCl and a saturated solution of NaHCO 3, dried over Na 2 SO 4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2 / piperidine, 4: 1 (5 milliliters) for 2 hours, the mixture is evaporated and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + acid 0.1 percent trifluoroacetic / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2C03, the CH3CN is removed at vacuum, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a yellowish solid. MS: 499.2 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.45 minutes. Example 62: ((3R * .5S *) - 5- (cyclopropyl-p - (3-methoxy-propyl) -1H-indol-3-yl-methyl-1-carbamoyl) -pperyl ester din-3-yl) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using isobutyl chloroformate. MS: 485.6 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.29 minutes. Example 63: cyclop ropi I - \ 1 - (3-m-ethoxy-propy 0-1 H-indol-3-yl-methylamide of (3S *. 5R *) - 5- (2,2-dimethyl- propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using pivaloyl chloride. MS: 469.6 [M + H] +. Example 64: Cyclopropyl-p - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide of (3S *, 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using tert-butyl acetyl chloride. MS: 483.6 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.02 minutes.
Example 65: Cyclopropyl-p - (3-methoxy-propyl) -1H-indol-3-yl-methylamide of (3S *, 5R *) - 5- (cyclobutyl-carbonyl-amino) -piperidin-3 acid -carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using cyclobutane-carbonyl chloride. MS: 467.5 [M + H] + * tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.79 minutes. Example 66: Cyclopropyl- [1- (3-methoxy-p ropil) -1 H-indol-3-ylmethyl-amide of (3S *, 5R *) - 5- (3-benzyl-ureido) - piperidin-3-carboxylic A mixture of the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl ester. { cyclopropyl- [1- (3-m-ethoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (91 milligrams, 0.15 millimoles), dichloroethane (2 milliliters), and benzyl isocyanate (18.4 microliters, 0.15 millimoles), is stirred for 14 hours at 50 ° C. A second portion of benzyl isocyanate (9.2 microliters, 0.075 mmol) is added, and stirring is continued for 5 hours at 60 ° C. The mixture is evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2 / piperidine, 4: 1 (5 milliliters) for 2 hours, the mixture is evaporated and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + acid 0.1 percent trifluoroacetic / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a yellow resin. MS: 518.3 [M + H] +? tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.05 minutes.
Example 67: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide of (3S *. 5R *) - 5- (3-cyclohexyl-ureido) -piperidin-3 acid -carboxylic The title compound is prepared in a manner analogous to that described in Example 66, using cyclohexyl isocyanate. MS: 510.5 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.15 minutes. Example 68: Cyclopropyl- [1- (3-methoxy-propyl) -1 H -indole (3S * .5R *) - 5- (3-tert-butyl) ureido) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 66, using terbutyl isocyanate. MS: 484.6 [M + H] +; tR (HPLC, column C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.94 minutes Example 69: Cyclopropyl-fl - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide of (3S *, 5R *) - 5-f2- (3-methoxy-phenyl) -acetyl- amino1-piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using 3-methoxy-phenyl-acetyl chloride. MS: 533.5 [M + H] +: tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.10 minutes. Example 70: Cyclopropyl-M - (3-methoxy-propyl) -1 H -indole-3-yl-met (3S *, 5R **) - 5-r (benzo-rbl-thiophene) 2-carbonyl) -amino-1-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using benzo- [b] -thiophene-2-carbonyl chloride. MS: 545.4 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.48 minutes Example 71: Cyclopropyl-1 - (3-methoxypropyl I) -1H-indol-3-yl-methyl-amide acid (3S *, 5R *) - 5- Benzoyl-amino-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using benzoyl chloride. MS: 489.3 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.99 minutes Example 72: Cyclopropyl-H - (3S *, 5R *) - 5-acetyl- (3-methoxypropyl) -1H-indol-3-yl-methylamide (3S *, 5R *) - 5-acetyl- amino-piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using acetyl chloride. MS: 427.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.33 minutes Example 73: Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol -3-yl-methyl-2-amide acid (3S *, 5R *) - 5 - (3,4-dimethoxy-benzoyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using 3,4-dimethoxy- chloride. benzoyl MS: 549.5 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.89 minutes Example 74: Ciclopropyl-H - (3-methoxy-propyl) -1H-indol-3-yl-metip-amide of (3S * .5R *) - 5- ( 3-Phenyl-propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using 3-phenyl-propionyl chloride. MS: 517.5 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.17 minutes.
Example 75: Cyclopropyl-H - (3-methoxy-propyl) -1H-indol-3-yl-methylamide of (3S *. 5R *) - 5- (cyclohexane-carbonyl-amino) -piperidin-3 acid -carboxylic twenty-one The title compound is prepared in a manner analogous to that described in Example 61, using cyclohexanecarbonyl chloride. MS: 495.6 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.22 minutes Example 76: Cyclopropyl-1 - (3-methoxy-propyl) -1H-indol-3-yl-methyl-1-amide acid (3S * .5R *) - 5- (3 -methyl-butyryl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using isovaleryl chloride. MS: 469.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.91 minutes Example 77: (3S *, 5R *) - 5- (2-ethyl-butyryl-amino) -piperidin cyclopropyl-ri- (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide-amide -3-carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using 2-ethylbutyryl chloride. MS: 483.7 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.05 minutes Example 78: Cyclopropyl-H - (3-? -neuroxypropyl) -1H-indol-3-yl-methyl-amide acid (3S *, 5R *) - 5 - [(2,2,3,3-tetramethyl-cyclopropane-carboniQ-amin or -piperidine-3-carboxylic A mixture of 2,2,3,3-tetramethyl-cyclopropane-carboxylic acid (50 milligrams, 0.35 mmol), 0- (1 H-6-chloro-benzotriazol-1-yl) -1, 1 hexafluoro-phosphate 3,3-tetramethyl uronium (HCTU) (145 milligrams, 0.35 mmol), N-ethyl-di-isopropyl-amine (171 microliters, 1 millimole) in CH 2 Cl 2 (3 milliliters), is stirred for 10 minutes at room temperature. After the addition of the acid (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (121.4 milligrams, 0.2 mmol) (starting material 6), stirring is continued for 14 hours. The mixture is diluted with CH 2 Cl 2, the organic layer is washed with a saturated solution of NaHCO 3, dried over Na 2 SO and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2 / piperidine, 4: 1 (5 milliliters) for 2 hours, the mixture is evaporated and the residue is purified by preparative HPLC (column C18)., 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a yellowish solid. MS: 509.6 [M + H] ": tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.68 minutes.
Example 79: Cyclopropyl-H - (3-methoxy-propyl) -1 H -indole (3S *. 5R *) - 5-y (tetrahydro-furan-2-) carbon-p-aminol-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using tetrahydro-furan-2-carbonyl chloride. MS: 483.6 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.61 minutes Example 80: Cyclopropyl-H - (3-methoxy-propyl) -1 H -indo I -3- and I -met i II-amide of the acid (3S *, 5R *) -5-isobutyryl-amino-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using isobutyryl chloride. MS: 455.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + acid 0.1 percent trifluoroacetic / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.75 minutes. Example 81: Cyclopropyl-H - (3S *, 5R *) - 5- (cyclopropane-carbonyl-amino) -piperidin-3- (3-methoxy-propy-1H-indol-3-yl-methyl-amide) carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using cyclopropanecarbonyl chloride. MS: 453.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.60 minutes Example 82: Cyclopropyl-M - (3-methoxy-ylpyl) -1 H-indol-3-yl-methylamide (3S * .5R *) - 5- (2-methoxy-acetylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using methoxy-acetyl chloride. MS: 457.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.43 minutes Example 83: Cyclopropyl-fl - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide acid (3S *, 5R *) - 5- ( 2-methyl-2-phenyl-propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using 2-methyl-2-phenyl-propionic acid. MS: 531.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.42 minutes Example 84: Cyclopropyl-fl-O-methoxy-propyl-1 H -indol -3- i I -met i II-amide of the acid (3S * .5R *) - 5- ((S) -2-acetylamino-4-methyl-pentanoylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using N-acetyl-L-leucine. MS: 540.6 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.71 minutes and 4.79 minutes (mixture of diastereomers) Example 85: Cyclopropyl-fl - (3-methoxypropyl) -1H-indol-3-yl-methylamide (3S *), 5R *) - 5 - [(1-acetyl-piperidin-4-carbonyl) -amino-1-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using 1-acetyl-piperidin-4-acid carboxylic MS: 538.6 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.31 minutes Example 86: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide of (3S *, 5R *) - 5- ( 2-dimethylamino-acetylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using N, N-dimethyl-glycine. MS: 470.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 3.88 minutes Example 87: Cyclopropyl- [1- (3-methoxy-propyl) -1 H -indo I -3- i I -methyl-amide of the acid (3S * .5R *) -5- (3-hydroxy-2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using 3-hydroxy-2,2-dimethyl-propionic acid. MS: 485.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.59 minutes Example 88: ((3R *, 5S * .- 5- { C-Chlopropyl-M- (3-methoxy-propyl) -1 H -indole-3-yl- Cyclopropane-1,1-dicarboxylic acid amide-methyla-carbamoyl) -piperidin-3-yl) -amide The title compound is prepared in a manner analogous to that described in Example 78, using 1-carbamoyl-cyclopropanecarboxylic acid. MS: 496.4 [M + H] +; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.23 minutes. Example 89: Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl-1-amide of (3S *, 5R *) - 5 - [(1-cyano-cyclopropane-carboniD-aminol -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 78, using 1-cyanopropanecarboxylic acid. MS: 478.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.69 minutes Example 90: Benzyl ester of ((3R *, 5S *) - 5- (cyclopropyl-M- (3-methoxy-propyl) -1 H-indol-3-yl acid ester -metill-carbamoyl) -piperidin-3-yl) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using benzyl chloroformate. MS (LC-MS): 519.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.39 minutes. Example 91: 2-methoxy ethyl ester of ((3R *. 5S * .- 5- (cyclopropyl-H - (3-methoxy-propyl) -1 H -indol-3-yl-methyl-carbamoyl) - pi peri di n-3-i I) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using 2-methoxy-ethyl chloroformate. MS (LC-MS): 487.7 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.68 minutes Example 92: r4-Chloro-3- (3-m-ethoxy-propoxy) -benzyl-1-cyclopropyl-amide acid (3S *, 5R *) - 5 - (2,2-dimethyl-propionyl-amine) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-carbamoyl} -piperidin-1-carboxylic acid, hydrochloride, and pivaloyl chloride. MS: 480.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.29 minutes The starting materials are prepared as follows: A. 9H-Fluoren-9-yl-methyl-ester of the acid (3R * .5S *) - 3-amino-5- (r4 -c-3- (3-methoxy-propoxy) -benzyl-cyclopropylcarba moi I) -piperidyl-1-carboxylic acid, hydrochloride A mixture of 1- (9H-fluoren-9-yl-methyl) - (3S *, 5R *) - 5-terbutoxycarbonyl-amino-piperidin-1,3-dicarboxylic acid ester (1.78 grams, 3.82 mmol), 0- (1 H-6-chloro) hexafluorophosphate benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium (1.75 grams, 4.23 mmol), and di-isopropyl-ethyl-amine (265.3 microliters, 1.55 mmol) in a 1: 1 mixture of CH2Cl2 CH3CN (20 milliliters) is stirred for 10 minutes at room temperature, after cooling to 5 [deg.] C., [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-amine is added. (1.04 grams, 3.86 millimoles) in one serving. The ice bath is removed, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with ethyl acetate and washed twice with a K2C03 solution. The organic layer is dried (Na2SO4) and evaporated. The crude oil obtained in this way is stir with HCl (5M in 2-propanol, 12 milliliters, 60 mmol) for 1 hour, and then evaporate, to give the title compound as a yellow oil. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.31 minutes. B. 4-Chloro-3- (3-methoxy-propoxy) -benzyl-propylamine A mixture of 4-chloro-3-hydroxy-benzoic acid (5 grams, 29 mmol) and sodium chloride. Thionyl (31 milliliters, 0.43 mol) in CH 2 Cl 2 / tetrahydrofuran (1: 1, 50 milliliters) is stirred for 2 hours at 50 ° C. The reaction mixture is evaporated in vacuo. After addition of CH 2 Cl 2 (50 milliliters), the mixture is cooled to 5 ° C, and treated by the dropwise addition of cyclopropyl-amine (8.1 milliliters, 115 mmol) for 1 hour. The cooling bath is removed, and the reaction is stirred for 14 hours at room temperature. After dilution with CH2Cl2, the organic phase is washed with a saturated solution of NaHCO3, and part of the solvent is removed in vacuo. The crystals thus formed are filtered and dried to provide 4-chloro-N-cyclopropyl-3-hydroxy-benzamide as white crystals. MS: 212.2 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.12 minutes N, N-dimethyl acetamide (50 milliliters) is added to the amide (4.6 grams, 21.7 millimoles), followed by K2C03 (4.8 grams, 34.7 millimoles) and 3-methoxy-propyl - toluene-4-sulfonic acid ester (6.89 grams, 28.2 millimoles). The mixture is stirred for 14 hours at 140 ° C, the N, N-dimethyl acetamide is removed in vacuo, and the residue is partitioned between ethyl acetate and H20. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried (Na2SO4) and evaporated to provide 4-chloro-N-cyclopropyl-3- (3-methoxy-propoxy) -benzamide as a brown oil, which crystallizes when maintained at room temperature. MS: 284.3 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.31 minutes The crude intermediate (3 grams, 10.6 millimoles) is diluted with tetrahydrofuran (28 milliliters), the mixture is stirred, cooled to -10 ° C, and treated by low drip N2 for 1 hour with a solution of borane-tetrahydrofuran complex (approximately 1M in tetrahydrofuran, 31.8 milliliters, 31.8 millimoles) The stirring is continued for 80 minutes at -10 ° C and for 14 hours at room temperature. quench with H20, acidify with 2N HCl, basify with 2N NaOH, and extract three times with ethyl acetate.The combined organic extracts are dried (Na2SO4) and evaporated The borane complex thus received is treated with methanol (40 milliliters) and kept for 6 hours at the reflux temperature, the methanol is distilled, and the residue is stirred for 10 minutes with 1N HCl. The mixture is basified with 1 N NaOH, and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporate, to give [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-amine as a yellow oil. MS: 270.3 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.43 minutes Example 93: Terbutil-acid ester ((3R *, 5S *) - 5- (f4-chloro-3- (3-methoxy-propoxy) -bencip-cyclopropyl-carbamoyl) -piperidine -3-il) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using 9H-fluoren-9-yl-methyl-ester of the acid (3 R *, 5S *) - 3-am i no-5- . { [4-chloro-3- (3-m-ethoxy-propoxy) -benzyl] I-cyclopropyl-carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 92 A) and diterbutyl dicarbonate. MS: 496.4 [M + H] "; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.41 minutes. Example 94: (3S *, 5R *) - 5- (Cyclopropane-carbonyl-amino) -piperidine-3-carboxylic acid-4-chloro-3- (3-methoxy-propoxy) -benzyl-H-cyclopropyl amide, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 61, using 9H-fluoren-9-yl-methyl-ester of the acid (3 R *, 5S *) - 3-am i no-5- . { [4-chloro-3- (3-m-ethoxy-propoxy) -benzyl] I-cyclopropyl-carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 92 A), and cyclopropane-carbonyl chloride. After the HPLC preparation, the pure fractions are evaporated without the addition of K2C03. MS: 464.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.95 minutes Example 95: [4-chloro-3- (3-m-ethoxy-propoxy) -benz II -cid opropyl-amide of (3S *, 5R *) - 5- (cyclobutan -carbonyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 92 A) and cyclobutane-carbonyl chloride. MS: 478.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.97 minutes Example 96: 4-chloro-3- (3-m-ethoxy-propoxy) -benz-11-cyclopropyl-amide acid (3S *, 5R *) - 5-isobutyryl-amino-piperidine -3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using 9H-fluoren-9-yl-methyl-ester of the acid (3 R *, 5S *) - 3-am i no-5- . { [4-chloro-3- (3-m-ethoxy-propoxy) -benzyl] -cyclopropyl-carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 92 A) and isobutyryl chloride. MS: 466.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 trifluoroacetic acid; percent / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.04 minutes. Example 97: [3-chloro-3- (3-m-ethoxy-propoxy) -benzyl-11-cyclopropyl-amide of (3S *, 5R *) - 5- (3-tert-butyl-ureido) -piperin-3 -carboxylic trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 98, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 92 A) and tertiary butyl isocyanate. After the HPLC preparation, the pure fractions are evaporated without the addition of K2C03. MS: 495.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.32 minutes Example 98: C opyl-T3- (3-methoxy-propoxy) -4-met i -benz II-amide of (3S *, 5R *) - 5- ( 3-terbutyl-ureido) -piperidine-3-carboxylic acid MW: 474.6490 MF: C26H42N404 NVP-BFQ579-NX-1 WB 5072/1 A mixture of the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl ester. { cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (110 milligrams, 0.173 millimoles), tertiary butyl isocyanate (40 microliters, 0.35 millimoles), di-isopropyl-ethyl-amine (34.2 microliters, 0.2 millimoles), and 1,2-dichloroethane ( 2 milliliters), is stirred for 14 hours at 50 ° C. The mixture is diluted with CH2Cl2 and washed with a solution of NaHCO3. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a CH2Cl2 / piperidine solution, 4: 1 (5 milliliters) for 1 hour, the mixture is evaporated, and the residue is purified by preparative HPLC (C18 column, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporate, to provide the title compound as a colorless resin. MS: 475.6 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.14 minutes The starting materials are prepared as follows: A. (3R *, 5S *) - 3-amino-5-fciclop ropil acid 9H-fluoren-9-yl-methyl ester - r3- (3-methoxy-propoxy) -4-methyl-benzyl-1-carbamoyl) -piperidin-1-carboxylic acid, hydrochloride The title compound is prepared in a manner analogous to that described in Example 92A, using the - (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid (9H-fluoren-9-ylmethyl) -ester and [3- (3-methoxy -propoxy) -4-methyl-benzyl] -amine MS: 598.6 [M + H] "; tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.35 minutes. B. Ciclop ropil- (3- (3-methoxy-propoxy) -4-methylbenzylamine The title compound is prepared in a manner analogous to that described in Example 92 B, starting from 3-hydroxy acid. 4-methyl-benzoic MS: 250.3 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.29 minutes.
Example 99: (3S *, 5R *) - 5- (3-benzyl-ureido) -piperidine-3-carboxylic acid cyclopropyl-3-3- (3-methoxy-propoxy) -4-methyl-benzyl-1-amide The title compound is prepared in a manner analogous to that described in Example 98, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 98 A) and benzyl isocyanate. MS: 509.6 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.22 minutes Example 100: Isobutyl ester of ((3R *, 5S *) - 5- (cyclopropyl-r3- (3-methoxy-propoxy) -4-methyl I -benzyl ester carb i love i) -pi pe ridi n-3-i I) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 98 A), and isobutyl chloroformate. MS: 476.6 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.40 minutes Example 101: Cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl-1-amide of (3S * .5R *) - 5- (2,2- dimethyl-propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 98 A), and pivaloyl chloride. MS: 460.6 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.07 minutes.
Example 102: (3S *, 5R *) - 5- (cyclobutane-carbonyl-amino) -p -peridin-3-carboxylic acid cyclopropyl-3-methoxy-3-methyl-benzylamide (3-methoxy-propoxy) -4-methyl-benzylamide The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 98 A), and cyclobutane-carbonyl chloride. MS: 458.7 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.88 minutes Example 103: Cyclopropyl 3-methoxy-5- (3-methoxy-propoxy) -benzyl-1-amide acid (3S *. 5R *) - 5- (3-tert-butyl-ureide ) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 98, using the (3R * 5S *) - 3-amino-5-9-fluoren-9-yl-methyl ester of the acid (3R * 5S *) -. { cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride, and tert-butyl isocyanate. After the HPLC preparation, the fractions are not basified before evaporation. MS: 491.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.75 minutes The star materials are prepared as follows: A. (3R *, 5S *) - 3-amino-5- (cyclop) 9H-Fluoren-9-yl-methyl-ester (3R *, 5S *) ropil- [3-methoxy-5- (3-methoxy-propoxy) -benzyl-1-carbamoyl I) -piperidin-1-carboxylic acid, hydrochloride The title compound is prepared in a manner analogous to that described in Example 92A, using 1 - (9H-Fluoren-9-yl-methyl) -ester (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid and cyclopropyl- [3-methoxy] 5- (3-methoxy-propoxy) -benzyl] -amine MS: 614.4 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.80 minutes. B. Cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzamine A mixture of 3-hydroxy-5-methoxy-benzoic acid methyl ester (4.71 grams, 25.9 mmol), K2C03 (5.72 grams, 41.4 millimoles), and 3-methoxy-propyl-ester of toluene-4-sulfonic acid (8.18 grams, 33.5 mmol) in N, N-dimethyl acetamide (60 milliliters), is stirred for 14 hours at 140 ° C. The mixture is partitioned between ethyl acetate and H20. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried (Na2SO) and evaporated to give the crude methyl 3-methoxy-5- (3-methoxy-propoxy) -benzoic acid methyl ester. MS: 255.3 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 6.12 minutes A mixture of 3-methoxy-5- (3-methoxy-propoxy) -benzoic acid methyl ester (6.94 grams, 27.3 mmol), aqueous 5N NaOH solution (25 milliliters, 125 mmol), and methanol (50 milliliters), is stirred for 1 hour at 50 ° C. The methanol is evaporated, and the residue is partitioned between 2N HCl and ethyl acetate.The aqueous layer is separated and extracted twice with Ethyl acetate The combined organic extracts are dried (Na2SO4) and evaporated to yield crude 3-methoxy-5- (3-methoxy-propoxy) -benzoic acid RT (HPLC, Nucleosil C18, 5-100 percent) of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.97 minutes A mixture of 3-methoxy-5 acid - (3-methoxy-propoxy) -benzoic acid (6.55 grams, 27.3 mmol), and thionyl chloride (19.8 milliliters, 273 mmol) in CH2Cl2 / tetrahydrofuran (1: 1; 30 milliliters), is stirred for 2 hours at 45 ° C. The reaction mixture is evaporated in vacuo. After the addition of CH2Cl2 (30 milliliters), the mixture is cooled to 5 ° C and treat by dripping with cyclopropyl-amine. The cooling bath is removed, and the reaction is stirred for 14 hours at room temperature. After dilution with CH 2 Cl 2, the organic phase is washed with a saturated solution of NaHCO 3, dried over Na 2 SO 4 and evaporated, to give N-cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzamide. MS: 280.3 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.79 minutes The N-cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzamide (7.92 grams, 28.4 mmol) is diluted with tetrahydrofuran (50 milliliters), the mixture it shakes, it is cooled to -10 ° C, and it is treated by the dropwise addition, under N2 for 1 hour, of a solution of borane-tetrahydrofuran complex (approximately 1M in tetrahydrofuran, 85.2 milliliters, 85.2 mmol). The cooling bath is removed, and stirring is continued for 14 hours at room temperature. The reaction is quenched with H20, acidified with 4N HCl, basified with 4N NaOH, and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated. The borane complex thus received is treated with methanol (60 milliliters), and maintained for 5 hours at the reflux temperature. The methanol is distilled, and the residue is stirred for a few minutes with 4N HCl. The mixture is basified with 4N NaOH, and extracted three times with ethyl acetate. The combined organic extracts are dried (Na 2 SO 4) and evaporated to give cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -amine as a brown oil. MS: 266.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 3.85 minutes Example 104: Cyclop ropil -T3-methoxy -5- (3-metoxy -propoxy) -benzyl-3-amide acid (3S *, 5R *) - 5- (3- benzyl ureido) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 98, using the (3 R * 5S *) - 3-am i no-5-9H-fluoren-9-yl-methyl ester. { cyclop ropil- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 103 A) and benzyl isocyanate. After the HPLC preparation, the fractions are not basified before evaporation. MS: 525.5 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.86 minutes.
Example 105: ((3R *, 5S *) - 5- (Cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzyl-carbamoyl) -pyridin-3-yl) -isobutyl ester carbamic, trifluoroacetate MW: 491.6332114.0243 MF: C26H41N306.C2HF302 NVP-BFQ886-AI-1 WB 5082/1 The title compound is prepared in a manner analogous to that described in Example 61, using the (3 R * 5S *) - 3-am i no-5-9H-fluoren-9-yl-methyl ester. { cyclop ropil - [3-m-ethoxy -5- (3-m-ethoxy-propoxy) -benzyl] -carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 103 A), and isobutyl chloroformate. After the HPLC preparation, the fractions are not basified before evaporation. MS: 492.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.05 minutes Example 106: ((3R *, 5S *) - 5-Cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzyl-1-carbamoyl) - tert-butyl ester - piperidin-3-yl) -carbamic The title compound is prepared in a manner analogous to that described in Example 61, using the (3R * 5S *) - 3-amino-5-9-fluoren-9-yl-methyl ester of the acid (3R * 5S *) -. { cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 103 A), and diterbutyl dicarbonate. MS: 492.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.01 minutes Example 107: Ciclop ropil -f-3-methoxy -5- (3-metoxy -propoxy) -benzyl (3S *, 5R *) - 5- (3 , 3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 61, using the 9H-fluoren-9-yl-methyl-ester of the acid (3 R * 5S *) - 3-am i no-5. { cyclop ropil- [3-methoxy-5- (3-m-ethoxy-propoxy) -benzyl] -carbamoyl} -piperidin-1-carboxylic acid, hydrochloride (Example 103 A), and tert-butyl-acetyl chloride. After the HPLC preparation, the fractions are not basified before evaporation. MS: 490.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.81 minutes Example 108: C The opropyl-3-m-ethoxy-5- (3-methoxy-propoxy) -benzyl-3-amide acid (3S *, 5R *) - 5- ( Cyclobutan-carbonyl-amino) -piperidine-3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 61, using the (3 R * 5S *) - 3-am i no-5-9H-fluoren-9-yl-methyl ester. { cyclop ropil - [3-m-ethoxy -5- (3-m-ethoxy-propoxy) -benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 103 A), and cyclobutane-carbonyl chloride. After the HPLC preparation, the fractions are not basified before evaporation. MS: 474.5 [M + H] "'tR (HPLC, Nucleosil C18; 5-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.53 minutes. Example 109: C i clop ropil -T3- methoxy -5- (3-methoxy-propoxy) -benzyl (3S *, 5R *) - 5- (2,2-dimethyl-propionyl-amino) -piperidine- 3-carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 61, using the (3R * 5S *) - 3-amino-5-9-fluoren-9-yl-methyl ester of the acid (3R * 5S *) -. { cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidine-1-carboxylic acid, hydrochloride (Example 103 A), and pivaloyl chloride. After the HPLC preparation, the fractions are not basified before evaporation. MS: 476.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.72 minutes Example 110: (3S **, 5R **) - 5- (3,3-dimethyl-butyryl-amino) cyclopropyl- (2,3-dichloro-benzyl) -amide. -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5- [cyclopropyl-] 9H-fluoren-9-yl-methyl ester. (2,3-dichloro-benzyl) -carbamoyl] -piperidin-1-carboxylic acid; hydrochloride, and tert-butyl-acetyl chloride. MS (LC-MS): 440.5 / 442.4 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid one hundred, for 8 minutes, flow: 1.5 milliliters / minute): 5.28 minutes The starting material is prepared as follows: A. 9H-Fluoren-9-yl-methyl-acid ester (3R * .5S *) - 3 -amino-5- [cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl-piperidine-1-carboxylic acid, hydrochloride To a frozen and stirred mixture of 1- (9H-fluoren-9-yl-methyl) - (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid ester (2.33 grams, 5 mmol), cyclopropyl- (2,3-dichloro-benzyl) -amine (see International Publication Number WO 03/093267) (1.12 grams, 5.2 mmol), and N-ethyl-di-isopropyl-amine (6.85 milliliters, 40 mmol) in dimethyl acetamide (30 milliliters), a solution of propyl anhydride is added -phosphonic (approximately 50 percent in N, N-dimethyl-formamide, 4.8 milliliters, approximately 7.5 thousand imoles) After stirring for 14 hours at room temperature, the N, N-dimethyl-acetamide evaporate, and the residue is partitioned between ethyl acetate and an aqueous solution of 10 percent K2C03 aqueous. The organic layer is dried (Na2SO4), evaporated in vacuo, and the residue is purified by preparative HPLC (YMC-Pack, Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with solid K2CO3, the CH3CN is removed in vacuo, and the residual aqueous layer is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is stirred with HCl in 2-propanol (5 N, 10 milliliters, 50 mmol) and evaporated to give the title compound as an amorphous white solid. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.22 minutes. Example 111: 2-methoxy-ethyl-ester of acid | (3R *, 5S *) - 5-cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl-piperidin-3-iU-carbamic acid The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5- [cyclopropyl-] 9H-fluoren-9-yl-methyl ester. (2,3-dichloro-benzyl) - carbamoyl] -piperidin-1-carboxylic acid, hydrochloride, and 2-methoxy-ethyl chloroformate. MS (LC-MS): 444.2 / 446.1 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 4.74 minutes. Example 112: ((3R *, 5S *) - 5-Cyclopropyl- (2,3-dimethyl-benzyl) -carbamoyl-p-peridin-3-iU-carbamic acid ester.
To a frozen and stirred mixture of the 1- (9H-fluoren-9-yl-methyl) -ester of the (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid (5.0 grams, 10.7 mmol), cyclopropyl- (2,3-dimethyl-benzyl) -amine (CAS 625437-38-9) (4.41 grams, 11.8 mmol), and N-ethyl-di-isopropyl-amine (14.7 milliliters, 85.7 millimoles) in dimethylacetamide (50 milliliters), a solution of propyl phosphonic anhydride (approximately 50 percent in N, N-dimethylformamide, 10 milliliters, approximately 16 mmol) is added, after stirring for 14 hours at room temperature, the residue is distributed between ethyl acetate and an aqueous 10% K2CO3 solution, the organic layer is dried (Na2SO4) and evaporated in vacuo, Part of the residue (365 milligrams, 0.58 mmol) is treated with a mixture of CH2Cl2. piperidine (4: 1, 10 milliliters), and it is stirred at room temperature for 1 hour, then the reaction mixture is evaporated, and the residue is purified by HPLC d. e preparation, to provide the title compound. MS: 402.5 [M + H] "'tR (HPLC, Nucleodur 100; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 10 minutes, flow: 1.5 milliliters / minute): 4.77 minutes Example 113: (3S *. 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidin-3-cyclopropyl- (2,3-dimethyl-benzyl) -amide. carboxylic acid, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5- [cyclopropyl-] 9H-fluoren-9-yl-methyl ester. (2,3-dimethyl-benzyl) -carbamoyl] -piperidine-1-carboxylic acid, hydrochloride, and tert-butyl-acetyl chloride. MS: 400.6 [M + H] "'tR (HPLC, Nucleodur 100, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 10 minutes, flow : 1.5 milliliters / minute): 8.6 minutes Starting material: A. (3R *, 5S *) - 3-amino-5-cyclopropyl- (2,3-dimethyl-) 9H-fluoren-9-yl-methyl-ester (3R *, 5S *) benzyl) -carbamoill-pi pe ridin-1 -carboxylic acid, hydrochloride The starting material is prepared in a manner analogous to described in Example 110 A, using the (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) -ester and cyclopropyl- (2,3-dimethyl-benzyl) -amine. MS: 524.5 [M + H]. "Starting materials 2A and 2B: Enantiomerically pure starting materials 1- (9H-Fluoren-9-yl-methyl) -ester of (3S *, 5R *) - 5- Racemic terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid (see Starting Material 2) is separated into its enantiomers on a Chiralcel OJ column with normal hexane / ethanol, 8: 2 (containing 0.1 trifluoroacetic acid) Accordingly, the (3R, 5S) -5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) -ester ester and the 1- (9S-Fluoren-9-yl-methyl) -ester (3S, 5R) -5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid Faster peak (Peak 1): tR (Chiralcel OJ; 80 percent normal hexane + 0.1 percent trifluoroacetic acid / 20 percent ethanol + 0.1 percent trifluoroacetic acid, for 30 minutes, flow: 1 milliliter / minute): 9.06 minutes Optical rotation : [a] D25 ° = - 8.2 (c = 1.0, CH3OH) Peak 2: tR (C hiralcel OJ, 80 percent normal hexane + 0.1 percent trifluoroacetic acid / 20 percent ethanol + 0.1 percent trifluoroacetic acid, for 30 minutes, flow: 1 milliliter / minute): 19.66 minutes. Optical rotation: [a] D25 ° = + 7.4 (c = 1.0, CH3OH).
Example 114: Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol -3-yl-methylamide of (3R.5S) -5- (2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic acid To a stirred mixture of the (3S, 5R) -3-amino-5-hydro-9-fluoren-9-M-methyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (374 milligrams, 0.62 mmol), N-ethyl-di-isopropyl-amine (503 microliters), 2.94 millimoles), and 4-dimethylaminopyridine (31 milligrams) in CH2Cl2 (8 milliliters), pivaloyl chloride (126 microliters, 1.02 millimoles) is added. After stirring for 14 hours at room temperature, the mixture is diluted with CH2Cl2. The organic layer is washed with 1N HCl and a saturated solution of NaHCO 3, dried over Na 2 SO 4, and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2 / piperidine, 4: 1 (6 milliliters) for 1 hour, the mixture is evaporated, and the residue is purified by prepara HPLC (YMC Pack Pro C18, 10-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K2C03, the CH3CN is removed in vacuo, and the The residual aqueous layer is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a yellowish resin. MS: 469.4 [M + H] "'t" (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow rate: 1.5 milliliters / minute): 5.03 minutes The starting material is prepared as follows: A. (3S, 5R) -3-amino-5-cyclopropyl-3-9-fluoren-9-yl-methyl-ester of the acid (3S, 5R) - (3-methoxy-propyl) -1H-indol-3-yl-methyl-carbamoyl) -piperidin-1-carboxylic acid A mixture of 1- (9H-fluoren-9-yl-methyl) -ester of (3R, 5S) -5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid (Example 114, peak 2) (401 milligrams, 0.86 mmol), 0- (1 H -6-chloro-benzotriazole-1 hexafluorophosphate) -yl) -1, 1, 3,3-tetramethyl-uronium (356 milligrams, 0.86 millimoles), and di-isopropyl-ethyl-amine (59.9 microliters, 0.35 millimoles), in a 1: 1 mixture of CH2Cl2 / CH3CN (6 milliliters) is stirred for 10 minutes at 5 ° C. Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amine (242 milligrams, 0.94 millimole) is added. in a portion, the ice bath is removed, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed twice with a K2C03 solution. The organic layer is dried (Na2SO4) and evaporated. To the residue is added CH2Cl2 (6 milliliters), and a freshly prepared solution of 2,6-lutidine (508) is added dropwise. microliters, 4.36 mmol) and tri-methyl-methanesulfonate of tri-methyl silyl (591 microliters, 3.27 mmol) in CH 2 Cl 2 (6 milliliters) for 5 minutes. The mixture is stirred at room temperature for 2 hours, diluted with CH 2 Cl 2 and washed with a saturated solution of NH 4 Cl and brine. The organic layer is dried over Na2SO4 and evaporated in vacuo to give the title compound as a brown oil. MS (LC-MS): 607.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 6.07 minutes Example 115: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol -3- and I -met i -amide of the acid (3R, 5S) -5- (3-tert-butyl-ureido) -piperidine-3-carboxylic acid A mixture of the (3S, 5R) -3-amino-5-9-fluoren-9-yl-methyl-ester ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (115 A) (374 milligrams, 0.62 mmol), dichloroethane (5 milliliters), and terbutyl isocyanate (142 microliters, 1.24 mmol), is stirred for 14 hours at 50 ° C. The mixture is diluted with CH2Cl2, and washed with 1N HCl and a saturated solution of NaHCO3. The organic layer is dried (Na2SO4) and evaporates The crude product is stirred with a solution of CH2Cl2 / piperidine, 4: 1 (6 milliliters) for 1 hour, the mixture is evaporated, and the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with K20O3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a yellow resin. MS: 484.2 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.05 minutes Example 116: Ethyl-f4- (3-methoxy-propyl) -3-oxo-3,4-dihydro-2H-benzo-f1, 41-oxazin-6-yl-1-amide acid (3S *, 5R *) - 5- (2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 61, using the (3R *, 5S *) - 3-amino-5-9-fluoren-9-yl-methyl-ester of the acid (3R *, 5S *) -. { ethyl- [4- (3-methoxy-propyl) -3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carba moi l} -piperid i n-1 -carboxyl, trifluoroacetate, and pivaloyl chloride. MS: 475.4 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 4.29 minutes The starting materials are prepared as follows: A. (3R *, 5S *) - 3-amino-5-fetil- 9H-fluoren-9-yl-methyl ester (3R *, 5S *) T4- (3-methoxy-propyI) -3-oxo-3,4-dihydro-2H-benzo-ri, 41-oxazin-6-n-carbamoyl) -p1peridn-1 carboxyl, trifluoroacetate The title compound is prepared in a manner analogous to that described in Example 92A, using the 1- (9H-fluoren-9-yl-methyl) -ester of (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid and 6-ethyl-amino-4- (3-methoxy-propyl) -4H-benzo- [1,4] -oxazin-3-one. product is purified by preparative HPLC (YMC Pack Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliter s / minute); tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.47 minutes. B. 6-ethyl-amino-4- (3-methoxy-propyl) -4H-benzo-f1, 41-oxazin-3-one A mixture of 6-nitro-4H-benzo- [1,4] -oxazin- 3-one (5 grams, 25.8 mmol) and NaH (approximately 60 percent wetted with oil, 911 milligrams, approximately 23 mmol) in N, N-dimethyl acetamide (30 milliliters), is stirred at 5 ° C for 30 minutes. minutes The 3-methoxy-propyl ester of the acid is added toluene-4-sulfonic acid (6.87 grams, 28.1 mmol) in N, N-dimethylacetamide (10 milliliters), followed by potassium iodide (4.67 grams, 28.1 mmol). The ice bath is removed and the mixture is stirred for 3 hours at 60 ° C. The solvent is distilled in vacuo, and the residue is partitioned between H20 and ethyl acetate. The organic layer is dried (Na2SO4) and the solvent is evaporated. Part of the crude product (5 grams, 18.8 mmol) is dissolved in a mixture of acetic acid (50 milliliters) and ethyl acetate (50 milliliters). The solution is added dropwise to a suspension of Fe powder (6 grams, 107 mmol) in 5 percent aqueous acetic acid (50 milliliters). The resulting mixture is maintained at 70 ° C for 5 hours. After cooling to room temperature, the Fe powder is filtered, and the filtrate is diluted with H20. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with a solution of NaHCO 3, dried (Na 2 SO 4), and evaporated. The residue is purified by column chromatography (SiO2, CH2Cl2 / CH3OH 100: 0-80: 20) to give 6-amino-4- (3-methoxy-propyl) -4H-benzo- [1,4] - Oxazin-3-one as a dark brown oil. MS: 237.3 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow 1.5 milliliters / minute): 2.66 minutes Part of this intermediate (1 gram, 4.2 millimoles) is diluted with methanol (15 milliliters) Acetaldehyde (166 microliters, 2.94 millimoles), acetic acid (480 microliters, 8.4 millimoles) are added , and NaBH3CN (396 milligrams, 6.3 mmol) The mixture is stirred for 1.5 hours at room temperature, quenched with a 5 percent KHS04 solution, and extracted with ethyl acetate. The organic layer is washed with a solution of NaHCO 3 and brine, dried over Na 2 SO 4 and evaporated in vacuo. Purification of the product by column chromatography (SiO 2, CH 2 Cl 2 / CH 3 OH) gives the title compound as a purple oil. MS: 265.3 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 3.41 minutes Example 117: (3S *, 5R *) - 5-rmethyl- (toluene-4-sulfonyl) -aminol-piperidine- (2,2-diphenyl-ethyl) -amide. 3-carboxylic, trifluoroacetate A mixture of (3S *, 5R *) - 5- [methyl- (toluene-4-sulfonyl) -amino] -piperidin-1,3-dicarboxylic acid ester (1-methyl-4-methyl ester) (40 milligrams, 0.097 mmol) and hexafluorophosphate of 0- (1 H -6-chloro-benzotriazol-1-yl) -1,1, 3,3-tetramethyl-uronium (44 milligrams, 0.107 mmol) in pyridine (1 milliliter) is stirred at room temperature for 15 minutes. minutes 2,2-Diphenylethylamine (21 milligrams, 0.107 is added millimoles), and the mixture is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 10 percent HCl, and the aqueous layer is extracted three times with methyl-tert-butyl ether. The combined organic extracts are dried (Na2SO), and the solvent is distilled. The residue is stirred with trifluoroacetic acid (0.965 milliliters) in CH2Cl2 (1 milliliter) for 1 hour, and then evaporated. The residue is purified by preparative HPLC (SunFire, 20-70 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 10 minutes, flow: 30 milliliters / minute) to provide the title compound. MS (LC-MS): 492.5 [M + H] "; tR (HPLC, Symmetry C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 7 minutes, flow: 1.5 milliliters / minute): 3.62 minutes The starting material is prepared as follows: A. (3S *, 5R *) - 5- [methyl- (toluene-4-thienylbutyl) ester -sulfonyl) -aminol-piperidin-1,3-dicarboxylic acid A mixture of (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-1, 3-tert-butyl ester dicarboxylic (Example 50 A) (150 milligrams, 0.376 mmol), K2C03 (0.52 grams, 3.76 mmol), and methyl iodide (0.234 milliliters, 3.76 mmol) in N, N-dimethylacetamide (3 milliliters), is stirred into a vessel Closed at 80 ° C for 14 hours.An aqueous solution of NaHS04 is added, and the mixture is extracted three times with methyl-tert-butyl ether.The combined organic layers are washed with a 5% Na2S203 solution. one hundred and brine, dried over Na2SO4 and evaporated in vacuo, to give the 3-methyl ester of (3S *, 5R *) - 5- [methyl- (toluene-4-sulfonyl) 1-tert-butyl ester) -amino] -piperidin-1,3-dicarboxylic acid. A mixture of this ester (160 milligrams, 0.375 millimoles), ethanol (4 milliliters), and 1N LiOH solution (1.88 milliliters, 1.88 millimoles) is stirred for 14 hours at room temperature. The mixture is diluted with H20 and extracted with methyl-tert-butyl ether. The organic layer is discarded, the aqueous phase is acidified to a pH of 2 with a 10 percent NaHS04 solution, and extracted three times with methyl tert-butyl ether. The combined organic extracts are dried (Na2SO4) and evaporated to give the title compound. MS (LC-MS): 413.4 [M + H] "; tR (HPLC, Symmetry C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 7 minutes, flow: 1.5 milliliters / minute): 4.31 minutes Example 118: (3S *, 5R *) - 5- (toluene-4-sulfonyl- (2-cyclohexyl-2-phenyl-ethyl) -amide) amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to described in Example 45, using 2-cyclohexyl-2-phenyl-ethyl-amine. MS: 484.2 [M + H] "'tR (HPLC, LiChrospher RP8; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2.5 minutes, flow: 1.5 milliliters / minute): 5.26 minutes Example 119: f2- (3-methoxy-methyl-phenyl) -2-phenyl-ethyl - (3S *, 5R *) - 5- (Toluene-4-sulfonyl-amine) -piperidine-3-carboxylic acid amide The title compound is prepared in a manner analogous to that described in Example 45, using 2- (3-methoxy-methyl-phenyl) -2-phenyl-ethyl-amine. MS: 522.2 [M + H] ": tR (HPLC, Lichrospher RP8, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow : 1.5 milliliters / minute): 4.77 minutes The starting 2- (3-methoxy-methyl-phenyl) -2-phenyl-ethyl-amine is prepared as follows: a) A solution of (3-methoxy-methyl-phenyl) ) -phenyl-acetonitrile (0.50 grams, 2.11 millimoles) in ethanol (10 milliliters) containing concentrated aqueous ammonia at 4 percent, is hydrogenated in the presence of Raney Nickel (0.2 grams) for 22 hours at room temperature. The mixture is filtered over Celite, washed with ethanol, followed by evaporation of the combined filtrates. The residue is purified by flash chromatography on silica gel (CH2Cl2 / MeOH / concentrated NH3, 95: 5: 0.5) to give the title product. MS: 242.1 [M + H] ": tR (HPLC, Nucleosil 100-5 R18; 10-100 percent trifluoroacetic acid CH3CN + 0.1 percent / H20 + 0.1 percent trifluoroacetic acid for 5 minutes, flow: 1.5 ml / min): 4.16 minutes Eiemplo 120: (2,2-diphenyl-butyl) -amide (3S *, 5R *) acid - 5- (toluene-4-sulfonylamino) -piper¡din. -3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 45, using 2,2-diphenyl-butyl-amine. MS: 506.2 [M + H] "; tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + trifluoroacetic acid at 0.1 percent / H20 + trifluoroacetic acid to 0.1 percent, for 5 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2.5 minutes, flow: 1.5 milliliters / minute): 5.11 minutes.
Eiemplo 121: r2- (4-chlorophenyl) -3-methyl-but¡p-carboxylic acid (3S * .5R *) - 5- (toluene-4-sulfonylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 45, using 2- (4-chloro-phenyl) -3-methyl-butyl-amine. MS: 478.1 / 480.1 [M + H] "; tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + trifluoroacetic acid at 0.1 percent / H20 + trifluoroacetic acid to 0.1 percent for 5 minutes then 100 percent CH3CN + trifluoroacetic acid to 0.1 percent, for 2.5 minutes, flow: 1.5 ml / min): 5.02 minutes Eiemplo 122:.. Ethyl ester of 2,2-diphenyl-3- { r (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carbonyl-aminol-propionic The title compound is prepared in a manner analogous to that described in Example 45, using the ethyl-ester of 3-amino-2,2-diphenyl-propionic acid, hydrochloride. MS: 550.2 [M + H] "; tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 4.96 minutes. Eiemplo 123: (4-methyl-2-phenyl-pentyl) -amide (3S *, 5R *) acid - 5- (toluene-4-sulfonylamino) -piperidin-3-yl carbox The title compound is prepared in a manner analogous to that described in Example 45, using 4-methyl-2-phenyl-pentylamine. MS: 458.2 [M + H] +: tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + trifluoroacetic acid at 0.1 percent / H20 + trifluoroacetic acid to 0.1 percent, for 5 minutes, flow : 1.5 milliliters / minute): 4.98 minutes. Eiemplo 124: (2- [2- (3-methoxy-propoxy) -fenill-2-phenyl-ethyl) -amide (3S *, 5R *) - 5- (toluene-4-sulfonylamino) -piperidine -3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 45, using 2- [2- (3-methoxy-propoxy) -phenyl] -2-phenyl-ethyl-amine. MS: 566.2 [M + H] "; tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + trifluoroacetic acid at 0.1 percent / H20 + trifluoroacetic acid to 0.1 percent, for 5 minutes, flow : 1.5 ml / min): 4.97 minutes The starting material 2- [2- (3-methoxy-propoxy) -phenyl] -2-phenyl-ethylamine is prepared as follows: a.) a solution of [2 - (3-methoxy-propoxy) -phenyl] -phenyl-acetonitrile (1.85 g, 6.58 mmol) in ethanol (30 ml) containing concentrated aqueous ammonia to 4 percent, it is hydrogenated in the presence of Raney nickel (1.85 grams ) for 8 hours at room temperature The mixture is filtered over Celite, washed with ethanol, followed by evaporation of the combined filtrates, to give the title product MS: 286.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 4.33 minutes. b) To a stirred solution of 1-benzyl-2- (3-methoxy-propoxy) -benzene (4.00 grams, 15.6 millimoles) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.25) grams, 18.7 millimoles) in CH2Cl2 (30 milliliters), tri-methyl cyanide is added (7.74 grams, 78.0 millimoles), and the reaction mixture is heated at 100 ° C for 1 hour in a reactor. microwave. After cooling to room temperature, the organics are washed with aqueous NaHC03 (10 percent) and water, dried (MgSO4) and concentrated. The product is purified by flash chromatography on silica gel (hexane / EtOAc, 97: 3 (1 liter), then hexane / EtOAc, 85:15), to give [2- (3-methoxy-propoxy) - phenyl] -phenyl-acetonitrile. MS: 282.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 5.43 minutes c) To a stirred solution of 2-benzyl-phenol (3.00 grams, 16. 2 millimoles) in acetonitrile (70 milliliters), K2C03 is added without water (3.38 grams, 24.4 millimoles) and 3-bromo-propyl-methyl-ether (3.74 grams, 24.4 millimoles). The mixture is refluxed overnight, filtered after cooling to room temperature, followed by evaporation of the filtrate. The residue is taken up in EtOAc, and the organic phase is subsequently washed with 0.5 M NaOH (100 milliliters), water, and brine. The combined organics are dried (MgSO4) and evaporated. The residue is purified by flash chromatography on silica gel (hexane / EtOAC, 93: 3), to give 1-benzyl-2- (3-methoxy-propoxy) -benzene. MS: 257.2 [M + H] ": tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 6.00 minutes.
Example 125: (3S *. 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid [2- (2-methoxy-pheny1) -2-phenyl-ethyl-1-amide The title compound is prepared in a manner analogous to that described in Example 45, using 2- (2-methoxy-phenyl) -2-phenyl-ethyl-amine. MS: 508.2 [M + H] "- tR (HPLC, Lichrospher RP8, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow : 1.5 milliliters / minute): 4.84 minutes Example 126: (3S *. 5R *) - 5- (toluene-4-sulfonyl-amino) (5-methoxy-2,2-diphenyl-pentyl) -amide piperidin-3-carboxylic The title compound is prepared in a manner analogous to described in Example 45, using 5-methoxy-2,2-diphenyl-pentylamine. MS: 550.2 [M + H] ": tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.35 minutes The starting material of 5-methoxy-2,2-diphenyl-pentylamine is prepared as follows: a) A solution of 5-methoxy-2,2-diphenyl-pentane- Nitrile (1.50 grams, 5.65 millimoles) in ethanol (25 milliliters), containing 4 percent concentrated aqueous ammonia, is hydrogenated in the presence of Raney Nickel (2.0 grams) for 20 hours at room temperature. Celite, washed with ethanol, followed by evaporation of the combined filtrates, to give the title product MS: 270.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 4.46 minutes. b) To a stirred mixture of NaH (60 percent in oil, 1.86 grams, 46.6 millimoles) in dimethylformamide (50 milliliters) at 0 ° C, a solution of diphenyl-acetonitrile (3.00 grams, 15.5 mmol) in dimethyl formamide (10 milliliters). The mixture is stirred for 30 minutes at room temperature, and then cooled to 0 ° C, followed by the dropwise addition of a solution of 3-bromo-propyl methyl ether (3.56 grams, 23.3 mmol) in dimethyl formamide. (10 milliliters). The mixture is stirred at temperature environment for 30 minutes, and then at 80 ° C for 15 minutes. After cooling to room temperature, the mixture is poured into ice water, followed by extraction of the aqueous phase twice with water. The organic phase is dried (MgSO 4), concentrated, and the residue is purified by flash chromatography on silica gel (eluent: CH 2 Cl 2) to give 5-methoxy-2,2-diphenyl-pentane-nitrile. MS: 266.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 5.53 minutes. Example 127: { 2-R 2 - (2-methoxy-ethoxy) -phen-H-2-phenyl-ethyl) -amide of (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidin-3 -amide Icy carboxy The title compound is prepared in a manner analogous to that described in Example 45, using 2- [2- (2-methoxy-ethoxy) -phenyl] -2-phenyl-ethyl-amine. MS: 552.2 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.13 minutes The starting material of 2- [2- (3-methoxy-ethoxy) -phenyl] -2-phenyl-ethyl- Amine is prepared as follows: a) A solution of [2- (3-methoxy-ethoxy) -phenyl] -phenyl-acetonitrile (1.46 grams, 5.46 mmol) in ethanol (25 milliliters) containing concentrated aqueous ammonia at 4 percent , hydrogenated in the presence of Raney Nickel (1.46 grams) for 6 hours at room temperature. The mixture is filtered over Celite and washed with ethanol, followed by evaporation of the combined filtrates, to give the title product. MS: 272.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 4.37 minutes b) To a stirred solution of 1-benzyl-2- (3-methoxy-ethoxy) -benzene (2.80 grams, 11.6 millimoles) and 2,3-dichloro-5 , 6-dicyano-1,4-benzoquinone (3.15 grams, 13.9 mmol) in CH2Cl2 (25 milliliters), trimethyl-1-silyl cyanide (5.73 grams, 57.8 mmol) is added, and the reaction mixture is heated to 100 C for 2 hours in a microwave reactor After cooling to room temperature, the organics are washed with aqueous NaHC03 (10 percent) and water, dried (MgSO4), and concentrated.The product is purified by chromatography by flash evaporation on silica gel (hexane / EtOAc, 97: 3 (1 liter), and then hexane / EtOAc 85:15), to give [2- (3-methoxy-ethoxy) -phenyl] -phenyl-acetonitrile MS: 268.2 [M + H] ": tR (HPLC, Nucleosil 100-5 R18; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 5 minutes, flow: 1.5 milliliters / minute): 5.25 minutes. c) To a stirred solution of 2-benzyl-phenol (3.00 grams, 16.3 mmol) in acetonitrile (70 milliliters), add K2C03 without water (3.38 grams, 24.4 mmol), and 2-bromo-propyl methyl ether. (3.40 grams, 24.4 millimoles). The mixture is refluxed overnight, and filtered after cooling to room temperature, followed by evaporation of the filtrate. The residue is taken up in EtOAc, and the organic phase is subsequently washed with 0.5 M NaOH (100 milliliters), water, and brine. The combined organics are dried (MgSO4) and evaporated. The residue is purified by flash chromatography on silica gel (hexane / EtOAC, 93: 3) to give 1-benzyl-2- (3-methoxy-ethoxy) -benzene. MS: 243.2 [M + H] "; tR (HPLC, Nucleosil 100-5 R18; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow: 1.5 milliliters / minute): 5.73 minutes Example 128: Terbutil-ester of acid f (3R * .5S *) - 5- [cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl -piperidin-3-ill-carbámic To a frozen and stirred mixture of 1 - (9H-fluoren-9-yl-methyl) - (3S *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid ester (300 milligrams, 0.643 mmol) in CH2Cl2 (7 milliliters), a 2M solution of N-ethyl is added -di-isopropyl-amine in 1-methyl-2-pyrrolidone (161 microliters, 0.322 mmol), followed by a solution of hexafluoro-phosphate of 0- (1 H -6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl uronium (HCTU) (292 milligrams, 0.707 millimoles) in CH3CN (7 milliliters). After 15 minutes, cyclopropyl- (2,3-dichloro-benzyl) -amine (139 milligrams, 0.643 mmol) is added. The mixture is stirred for 15 minutes at 0 ° C and for 14 hours at room temperature. After evaporation of the solvents in vacuo, the residue is diluted with CH2Cl2 and washed with an aqueous solution of 10% K2C03., a 2M HCl solution, and brine. The organic layer is dried over Na 2 SO 4, evaporated in vacuo, and the residue is purified by flash chromatography (SiO 2, CH 2 Cl 2 / acetone, 96: 4). Part of the crude product (50 milligrams, 0.075 millimoles) is dissolved in CH2CI2 (1 milliliter), treated with piperidine (0.222 milliliters, 2.25 millimoles), and stirred for 1 hour at room temperature. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with solid K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are Dry (Na2SO4) and evaporate to give the title compound as a colorless foam. MS: 442.2 / 444.2 [M + H] "'tR (HPLC, Lichrospher RP8, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2.5 minutes, flow: 1.5 milliliters / minute): 5.08 minutes Example 129: (3S-2,3-di-phenyl-propyl) -amide *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 45, using 3-chloro-benzenesulfonyl chloride in place of 4-toluenesulfonyl chloride, and 2,3-diphenyl-propyl amine as the amine component. MS: 512.2 / 514.2 [M + H] "'tR (HPLC, Lichrospher RP8, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes , then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2.5 minutes, flow 1.5 milliliters / minute): 6.24 minutes Example 130: cyclopropyl- (2,3-dichloro-benzyl) -amide (3S) *, 5R *) - 5- (toluene-4-sulfo nyl-amino) -piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 54, using 0- (1H-6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluoro-phosphate. (HCTU) for the condensation step, and cyclopropyl- (2,3-dichloro-benzyl) -amine as the amine component. MS: 496.0 / 498.0 [M + H] "; tR (HPLC, Lichrospher RP8; 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, flow : 1.5 milliliters / minute): 4.90 minutes Example 131: Terbutil-acid ester | (3R *, 5R *) - 5-cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl-1-piperidin-3-yl) - carbamic To a frozen and stirred mixture of (3R *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1 - (9H-fluoren-9-ylmethyl) ester (233 milligrams , 0.5 mmol), cyclopropyl- (2,3-dichloro-benzyl) -amine (112 milligrams, 0.52 mmol), and N-ethyl-di-isopropyl- amine (685 microliters, 4 millimoles) in dimethyl acetamide (3 milliliters), a solution of propyl phosphonic anhydride (approximately 50 percent in N, N-dimethylformamide, 0.48 milliliters, approximately 0.75 millimole) is added. The mixture is stirred for 14 hours at room temperature. After evaporation of the solvent in vacuo, the residue is diluted with ethyl acetate and washed with an aqueous solution of 10 percent K2C03 and brine. The organic layer is dried over Na2SO4, evaporated in vacuo, and the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoro- acid). acetic at 0.1 percent, 20 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with solid K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the (3R *, 5R *) - 3-terbutoxy-carbonyl-amino-5- [cyclopropyl- (9H-fluoren-9-yl-methyl ester) ( 2,3-dichloro-benzyl) -carbamoyl] -piperidine-1-carboxylic acid as a colorless oil. tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 2 minutes, flow: 1.5 milliliters / minute): 8.45 minutes. The product is dissolved in CH2Cl2 / piperidine 4: 1 (5 milliliters), and stirred for 1 hour at room temperature. After evaporation under vacuum, the residue is purified by Preparation HPLC (YMC Pack Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, 30 minutes, flow: 20 milliliters / minute). The combined pure fractions are treated with solid K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound as a colorless resin. MS: 442.3 / 444.2 [M + H] "'tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow: 1.5 milliliters / minute): 5.58 minutes. Example 132: (3R *, 5R *) - 5- (3-chloroben-n-sulfonyl-amino) -piperidine-3-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) -amide The title compound is prepared in a manner analogous to that described in Example 54, using cyclopropyl- (2,3-dichloro-benzyl) -amine. MS: 516.2 / 518.1 [M + H] "'tR (HPLC, Nucleosil C18, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes , flow: 1.5 milliliters / minute): 5.74 minutes Example 133: Terbutil-acid ester ((3R *, 5R *) - 5- (cyclopropyl- [1- (3-methoxy-propyl) -1H-indole- 3-yl-methyl-1-carbamoyl) -piperidin-3-yl) -carbamic acid An ice-cold mixture of (3R *, 5R *) - 5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) ester (93.3 milligrams, 0.2 mmol), 0- (1 H -6-chloro-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluoro-phosphate (HCTU) (91 milligrams, 0.22 mmol), and ethyl- di-isopropyl-amine (17.1 microliters, 0.1 mmol) in CH2Cl2 / CH3CN, 1: 1 (2 milliliters), is stirred for 10 minutes. Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amine (51.7 milligrams, 0.2 mmol) in CH2Cl2 / CH3CN, 1: 1 (1 milliliter) is added, and the The mixture is stirred for 14 hours at room temperature. The mixture is diluted with ethyl acetate, and washed twice with a K2C03 solution. The organic layer is dried over Na2SO4 and evaporated in vacuo. The crude product is treated with CH 2 Cl 2 / piperidine, 4: 1 (5 milliliters), and stirred for 1 hour at room temperature. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, flow : 20 milliliters / minute). The combined pure fractions are treated with solid K2CO3, the CH3CN is removed in vacuo, and the residual aqueous phase is extracted two. times with CH2CI2. The combined organic layers are dried (Na2SO4) and evaporated to give the title compound. MS: 485.5 [M + H] "; tR (HPLC, Nucleosil C18; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 8 minutes, flow : 1.5 milliliters / minute): 5.33 minutes.
Scheme 8 ? / - (2-mercaptoethyl) amino-ethyl-polystyrene, DBU Example 134: cyclopropyl-4 - (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-in-amide acid (3R) , 5S) -5-Phenyl-acetyl-amino-piperidine-3-carboxylic acid 9H-Fluoren-9-yl-methyl-ester of (3R, 5S) -3- acid. { cyclopropyl- [4- (3-methoxy-propi I) -2,2-di methi I-3-oxo-3, 4-dih id ro-2H -be nzo- [1,4] -oxazin-6-yl ] -carbamoil} -5-f-l-acetyl-amino-piperidin-1-carboxylic acid (90 milligrams, 0.12 mmol) is treated with 4N HCl / AcOEt (2 milliliters) at room temperature for 1 hour, and then evaporated. The evaporated residue is dissolved in CH2Cl2 (1 milliliter). To the solution are added phenyl-acetyl chloride (20.4 milligrams, 0.132 millimoles) and di-isopropyl-ethyl-amine (32 milligrams, 0.264 millimoles) at 0 ° C, and stirred for 40 minutes. After adding 1 N aqueous HCl, the mixture is extracted with CH 2 Cl 2, washed with saturated aqueous NaHCO 3, brine, and dried (MgSO 4). It is concentrated in vacuo, and the evaporated residue is dissolved in tetrahydrofuran (1 milliliter). To the solution are added DBU (9 milligrams, 0.06 millimoles) and N- (2-mercapto-ethyl) -amino-ethyl-polystyrene (2.1 millimoles / gram, 286 milligrams, 0.6 millimoles), and it is stirred for 1 hour at room temperature. The reaction mixture is filtered through a pad of Celite, and washed with tetrahydrofuran. Concentration in vacuo and purification with RP-HPLC give the title compound. MS: 549 [M + H] "; t" (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 trifluoroacetic acid one hundred, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.78 minutes. The starting material is prepared as follows: A. (3R.5S) -3- (cyclopropyl-4 - (3-methoxypropyl) -2H-fluoren-9-ylmethyl ester, 2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4-oxazin-6-i-ll-carbamoi I) -5-phen i-acetyl-am i no-pipe rid i n -1-carboxylic acid To a solution of acid 1- (9H-fluoren-9-yl-methyl) -ester (3R, 5S) -5-terbutoxy-carbonyl-amino-piperidin-1,3-dicarboxylic acid (338 milligrams, 0.73 mmol) in tetrahydrofuran (5.0 milliliters), chloroformate of sobutyl (0.1 milliliter, 0.79 mmol) and Et3N (0.1 milliliters, 0.79 mmol) at 0 ° C. After stirring for 1 hour at the same temperature, the resulting precipitate is filtered, and the filtrate is concentrated. The evaporated residue is dissolved in tetrahydrofuran (5 milliliters), and 6-cyclopropyl-amino-4- (3-methoxy-propyl) -2,2-dimethyl-4H-benzo- [1,4] -oxazin-3 is added. -one (200 milligrams, 0.66 millimoles) and MgBr2-OEt2 (189 milligrams, 0.73 millimoles) at room temperature. After stirring for 2 hours, the reaction is quenched with H20, and the resulting mixture is extracted with AcOEt, washed with a solution of 1N HCl, saturated aqueous NaHCO3, and brine. The organic layer is dried (MgSO 4), concentrated, and purified by silica gel column chromatography, to provide the title compound as a solid. amorphous white MS: 753 [M + H] "; tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid , for 5 minutes then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 4.77 minutes The amine used in Example 134A is prepared as follows: B. 6 -cyclopropyl-amino-4- (3-methoxy-propyl) -2,2-dimethyl-4H-benzo- [1,4-oxazin-3-one At room temperature, a solution of 2-amino-4-nitro- phenol (82.5 grams, 0.54 moles) in dimethyl formamide (660 milliliters), treated with ethyl 2-bromoisobutyrate (160 milliliters, 1.07 moles) and KF (124.7 grams, 2.15 moles), is stirred at the same temperature during 1 hour, it is heated to 60 ° C, and stirred for 48 hours. After pouring the mixture into H20 (3500 milliliters), the resulting precipitate is collected by filtration, and washed with H20 and Et20 several times, respectively, to give 2,2-dimethyl-6-nitro-4H-benzo- [ 1,4] -oxazin-3-one (84.8 grams, 71 percent) as a yellow solid. R, (hexane / EtOAc 2: 1) 0.42. 1 H-NMR (400 MHz, DMSO-d 6) 1.48 (s), 7.16 (d, J = 9.0), 6.42 (cf, J = 0.4), 8.00 (dd, J = 9.0, 0.4). 13 C-NMR (100 MHz, DMSO-d 6) 167.7 (s), 147.5 (s), 142.0 (s), 128.0 (s), 119.2 (d), 117.3 (d), 110.3 (d), 78.9 (s) , 23.7 (2g). At 0 ° C, a solution of 2,2-dimethyl-6-nitro-4H-benzo- [1,4] -oxazin-3-one (35.8 grams, 0.161 moles) and 1-methoxy-3- (p-) toluenesulphonyloxy) -propane (47.6 grams, 0.195 moles) in dimethyl formamide (720 milliliters), it is treated with Kl (5.49 grams, 33.1 millimoles). After adding 60 percent NaH (7.80 grams, 0.195 moles) for 10 minutes, the mixture is stirred at 0 ° C for 30 minutes, heated to 60 ° C, stirred for 14 hours, and treated with H20. (3500 milliliters). After extraction of the mixture with EtOAc (400 milliliters, 3 times) and Et20 (400 milliliters, 3 times), the combined organic layer is washed with H20 (250 milliliters, 2 times), dried (Na2SO4), and evaporates Flash chromatography with Si02 (2,000 grams, hexane / EtOAc, 5: 2) gives 4- (3-methoxy-propyl) -2,2-dimethyl-6-nitro-4H-benzo- [1,4] -oxazin-3-one (39.0 grams, 82 percent) as a yellow oil. Rf (hexane / EtOAc 5: 2) 0.45. 1 H-NMR (400 MHz, CDCl 3) 1.55 (s), 1.91-2.02 (m, 2 H), 3.36 (s), 3.43 (t, J = 6.0), 4.07 (t, J = 6.0), 7.04 (d , J = 9.0), 7.93 (dd, J = 9.0, 0.4), 8.09 (d, J = 0.4). 13 C-NMR (100 MHz, CDCl 3) 167.6 (s), 148.9 (s), 143.0 (s), 129.5 (s), 119.8 (cf), 117.7 (cf), 110.4 (d), 78.9 (s), 69.4 (i), 58.7 (q), 39.7 (f), 27.5 (f), 23.7 (2q). At room temperature, an ethanolic solution (80 milliliters) of the 4- (3-methoxy-propyl) -2,2-dimethyl-6-nitro-4H-benzo- [1,4] -oxazin-3-one ( 9.76 grams, 33.2 millimoles), treated with H20 (80 milliliters), NH CI (3.58 grams, 66.9 millimoles), and Zn powder (10.97 grams, 0.17 moles), heated to 80 ° C, stirred for 2 hours under reflux, it is cooled to room temperature, and filtered through a pad of Celite. After washing the cake with CH2Cl2 several times, both layers of the combined filtrate are separated. The aqueous layer is treated with 5N NaOH (6.0 milliliters) to adjust its pH of 9 to about 10, and extracted with CH2Cl2 (100 milliliters, 3 times). The combined organic layer is washed with a saturated aqueous solution of NaHCO 3 (100 milliliters) and brine (50 milliliters), dried (Na 2 SO 4), and evaporated. Flash chromatography with Si02 (250 grams, CH2Cl2 / acetone, 3: 1) gives 6-amino-4- (3-methoxy-propyl) -2,2-dimethyl-4H-benzo- [1, 4] -oxazin-3-one (9.23 grams, 99 percent) as a brown oil. Rf (CH2Cl2 / EtOAc 2: 1) 0.34. 1 H-NMR (400 MHz, CDCl 3) 1.39 (s), 1.80 -1.91 (m, 2 H), 3.28 (s), 3.35 (t, J = 8.0), 3.44 (br. S), 3.88 (t, J = 9.0), 6.23 (dd, J = 9.0, 0.4), 6.33 (d, J = 0.4), 6.68 (d, J = 9.0). At room temperature, a methanolic solution (33 milliliters) of 6-amino-4- (3-methoxy-propyl) -2,2-dimethyl-4H-benzo- [1,4] -oxazin-3-one (4.13 grams, 15.6 millimoles) is treated with AcOH (8.3 milliliters) and [(1-ethoxy-cyclopropyl) -oxy] -trimethyl-silane (3.1 milliliters, 15.6 millimoles), heated to 70 ° C, stirred for 1.5 hours under Reflux. At the same temperature, a methanolic solution (5.5 milliliters) of NaBH3CN (1.10 grams, 17.5 mmol) was added dropwise over this mixture for 5 minutes, and the resulting mixture was stirred at 70 ° C under reflux for 2 hours, and treated with CH2Cl2 (100 milliliters) and 5N NaOH (50 milliliters). After separation of both layers, the aqueous layer is extracted with CH2Cl2 (30 milliliters, 3 times). The combined organic layer is washed with brine (50 milliliters), dried (Na2SO4), and evaporated. Flash chromatography with Si02 (200 grams, hexane / EtOAc, 3: 2) gives the title compound (3.03 grams, 64 percent) as a light yellow solid. R, (hexane / EtOAc 3: 2) 0.48. 1 H-NMR (400 MHz, CDCl 3) 0.47-0.54 (m, 2 H), 0.68-0.73 (m, 2 H), 1.55 (s), 1.88 -1.96 (m, 2 H), 2.36-2.43 (m, 1 H), 3.34 (s), 3.44 (t, J = 6.0), 3.97 (t, J = 9.0), 4.09 (br. S), 6.45 (dd, J = 9.0, 0.4), 6.53 (d, J = 0.4), 6.80 (d, J = 9.0). 13 C-NMR (100 MHz, CDCl 3) 169.2 (s), 144.3 (s), 135.5 (s), 129.6 (s), 118.1 (d), 107.9 (d), 99.9 (d), 77.2 (s), 70.1 (t), 58.7 (q), 39.2 (t), 27.6 (i), 25.7 (d), 23.6 (2q), 7.3 (2f). Example 135: C iclop ropil -f4- (3-methoxypropyl I) -2.2-di methyl-3-oxo-3,4-dihydro-2H-benzo- [1.41-oxazin-6-ill-amide acid] (3R, 5S) -5- (2-phenoxy-acetylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using phenoxy-acetyl chloride. MS: 565 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1-7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + acid trifluoroacetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.87 minutes.
Example 136: C i cio prop i I - [4- (3-methoxypropyl) -2,2-di methyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6 (3R.5S) -5 - [(1 • Phenyl-cyclopropane-carbonyl) -amino-piperidine-3-carboxylic acid-n-amide The title compound is prepared in a manner analogous to that described in Example 134, using 1-phenyl-1-cyclopropyl-carboxylic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 575 [M + H] +: tR (HPLC, ACQUITY UPLCMR BEH Cie 1-7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + acid trifluoro-acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.02 minutes. Example 137: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-ri, 41-oxazin-6-yl-amide of (3R, 5S) acid ) -5- (2-h id roxi -4-meti l-pentano i l-am i no) -pipe ridi n-3-carboxyl The title compound is prepared in a manner analogous to that described in Example 134, using DL-leucic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 545 [M + H] "; t" (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + acid 0.1 percent trifluoroacetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.64, 2.74 minutes Example 138: C iclop ropil -T4- (3-methoxypropyl I) -2.2-di meti I -3 - (3R, 5S) -5- (2-hydroxy-3-phenyl-propionyl-amino) -piperidine-3-dihydro-2H-benzo-p, 41-oxazin-6-ill-amide 3-carboxylic The title compound is prepared in a manner analogous to that described in Example 134, using DL-phenyl-lactic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 579 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH Cie 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + trifluoro- acid 0.1% acetic / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.70, 2.81 minutes. Example 139: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-d-methyl-3-oxo-3,4-dihydro-2H-benzo-l, 41-oxazin-6-ill-amide of (3R, 5S) -5- (2-hydroxy-3-methyl-butyryl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using DL-Valic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 531 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.49, 2.93 minutes Example 140: C opropyl - [4- (3-m ethoxy -p ropil) -2, 2-di meti I 3-Oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-yl-1-amide of (3R, 5S) -5-f2- (tetrahyd ro-pi ran-4-yloxy) -acetyl-amino-1-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using [(tetrahydro-2H-pyran-4-yl) -oxy] -acetic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 573 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.46 minutes Example 141: Tetrahydro-pyran-4-yl-ester acid ((3S, 5R) -5-. - [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4-oxazin-6- i II -carbamoyl] -piperid i n- 3- i I) -carbamic The title compound is prepared in a manner analogous to that described in Example 134, using tetrahydro-2H-pyran-4-yl-ester of carbonchloride acid. MS: 599 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C? 8 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.53 minutes. Example 142: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-f1, 41-oxazin-6-ill-amide of acid (3R) , 5S) -5- (2-hydroxy-methyl-3-methyl-butyryl-amino) -piperidine-3-carboxylic acid The title compound is prepared by deprotection of Fmoc of the (3R, 5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -5- (2-hydroxy-methyl-3-methyl-butyryl-amino) -piperidine-1-carboxylic acid, in a manner analogous to that described in Example 134. MS: 545 [M + H] ": tR (HPLC , ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.43, 2.61 minutes. The starting materials are prepared as follows: A. (3R, 5S) -3- (cyclopropyl-4 - (3-methoxy-propyl) -2,2-dimethyl-9H-fluoren-9-yl-methyl ester. -3-oxo-3,4-dihydro-2H-benzo-ri, 41-oxazin-6-ill-carbamoyl) -5- (2-hydroxy-methyl-3-methyl-butyryl-amino) -piperidin-1- carboxylic acid To a solution of the (3R, 5S) -3- 9H-fluoren-9-yl-methyl ester. { cyclopropyl - [4- (3-methoxy-propyI) -2,2-di-methyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl ] -carbamoil} -5- [3-Methyl-2- (2-trimethyl-silanyl-ethoxy-methyl) -butyryl-amino] -piperidine-1-carboxylic acid in CH2Cl2 is added with BF3 Et20 at room temperature, and then the mixture is stirred at room temperature. room temperature. After 1.5 hours, the reaction mixture is diluted with H20 (10 milliliters) and extracted with CH2Cl2 (20 milliliters). The organic phase is washed with 5 percent aqueous KHS04 (10 milliliters), 5 percent aqueous NaHCO3, H20, and brine, and then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to give the title compound as an amorphous white material. MS: 767 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 trifluoroacetic acid percent / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 1.55 minutes. B. (3R.5S) -3- (Cyclopropyl-r4- (3-methoxy-propyl) -2, 2-di methyl I -3-0X0-3 9H-Fluoren-9-yl-methyl ester , 4-dih id ro-2H- be nzo- [1,4-oxazin-6-ill-carbamoyl) -5-r3-methyl-2- (2-trimethyl-silanyl-ethoxy-methyl) -butyryl-aminol- piperidin-1-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using 3-methyl-2- (2-trimethyl-silanyl-ethoxy-methyl) -butyric acid as the acid component , and EDCI and HOAt for the acylation step. MS: 867 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 5.21 minutes C. 3-Methyl-2- (2-trimethyl-silanyl-ethoxy-methyl) -butyric acid To a solution of ethyl ester of 3-methyl-butyric acid (1.3 grams, 10 mmol) in tetrahydrofuran (50 milliliters), a solution of LDA (2 M in tetrahydrofuran / hexane / ethylbenzene, 6 mmol) is added dropwise to -78. ° C, and the mixture is stirred to -78 ° C. After 0.5 hours, (2-chloro-methoxy-ethyl) -trimethyl-silane (2.65 milliliters, 15 mmol) is added at -78 ° C to the reaction mixture. The reaction mixture is allowed to warm to 0 ° C for 2 hours, and then quenched by the addition of 100 milliliters of 5% aqueous KHS04., and extracted with Et20 (200 milliliters). The organic phase is washed successively with 5 percent aqueous KHS04, 5 percent aqueous NaHCO3, H20, and brine, then dried over NaSO4 and concentrated under reduced pressure. A mixture of the residue and aqueous 1M NaOH in methanol is stirred at 70 ° C. After 5 hours at 70 ° C, the reaction mixture is quenched with 5 percent aqueous KHS0 (100 milliliters) and extracted with Et20 (200 milliliters). The organic phase is washed successively with H20, and brine, and then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to provide the title compound. Example 143: ((3S, 5R) -5- (cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-ri) -butyl ester, 41-oxazin-6-ill-carbamoyl-piperidin-3-yl) -carbamic acid The title compound is prepared by deprotection of Fmoc from Example 134A, as described in Example 134. MS: 599 [M + H] "'tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters; percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.70 minutes. Example 144: Ciclop ropil- r4- (3-methoxy-p ropil) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4-oxazin-6-ill-acid amide ( 3R, 5S) -5-acetyl-amino-piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 134, using acetic anhydride. MS: 473 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.33 minutes Example 145: Cyclopropyl-f4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro- 2H-Benzo-p.41-oxazin-6-in-amide of (3R, 5S) -5- [2- (piperidon -3- i I oxy) -acetyl-nano-pipe-ridine n-3 -lolly box The title compound is prepared in a manner analogous to that described in Example 134, using the (pyridin-3-yloxy) -acetic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 566 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.24 minutes The starting materials are prepared as follows: A. Acid (pyridin-3-yloxy) -acetic A mixture of the terbutil-acid ester (pyridine 3-yloxy) -acetic (60 milligrams, 0.29 mmol) and HCl in dioxane (4 M, 2 milliliters) is stirred at room temperature for 1 hour.The reaction mixture is concentrated in vacuo to give the title compound. : 154 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 trifluoroacetic acid one hundred, for 1.5 minutes, flow: 0.5 milliliters / minute): 0.40 minutes. B. Terbutil- (pyridin-3-yloxy) -acetic acid ester A mixture of tert-butyl bromoacetate (2 grams, 10 mmol), 3-hydroxy-pyridine (1.5 grams, 15 mmol), and K2C03 (2.9 grams, 21 millimoles) in tetrahydrofuran (20 milliliters), is stirred at 60 ° C. After 0.5 hours, the reaction mixture is cooled to room temperature and diluted with H20, and then extracted with EtOAc. The organic phase is washed with H20, and brine, and then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give the title compound. MS: 210 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C1ß 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 1.85 minutes Example 146: Cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4 2-dihydro-2H-benzo-p, 41-oxazin-6-ill-amide of (3R, 5S) -5- (2- tetrahydro-pyran-4-yl-acetylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using the acid (tetrahydro-pyran-4-yl) -acetic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 557 [M + H] ": tR (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoric acid -acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.78 minutes Example 147: C iclopropyl-r4- (3-methoxy-p ropil) -2, 2-di meti l-3-oxo -3,4-dihydro-2H-benzo-p, (3R, 5S) -5- (3-hydroxy-3-methyl-butyryl-amino) -piperidin-3-3-oxazin-6-yl-amide carboxylic The title compound is prepared in a manner analogous to described in Example 134, using 3-hydroxy-3-methyl-butyric acid as the acid component, and EDCI and HOAt for the acylation step. MS: 531 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.46 minutes, Example 148: C i clop ropil - [4 - (3-methoxypropyl I) -2.2-di-methyl-3-oxo-3,4-dihydro-2H-benzop, (3R, 5S) -5-f-3-oxazin-6-in-amide (tetrahydro-pyran-4-carbonyl) -aminol-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using tetrahydro-pyran-4-carboxylic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 543 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 2 minutes, then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.48 minutes.
Example 149: N - ((3S.5R) -5- (cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-ri, 41 -oxazin-6-ill -carbamoi I) -piperidin-3-yl) -nicotinamida The title compound is prepared in a manner analogous to that described in Example 134, using nicotinic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 536 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.41 minutes Example 150: Cyclopropyl-4- (3- (3R, 5S) -5-methanesulfonyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p.41-oxazin-6-yn-amide -amino-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using methansulfonyl chloride. MS: 509 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoroacetic acid 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.44 minutes Example 151: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro- 2H-Benzo-p, (3R, 5S) -5- (2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic acid-41-oxazin-6 -n-amide The title compound is prepared in a manner analogous to that described in Example 134, using pivaloyl chloride. MS: 515 [M + H] "; tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid , for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.54 minutes.
Example 152: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p.41-oxazin-6-yl-1-amide acid (3R) , 5S) -5-y (1 • cyano-cyclopropan-ca rbonyl) -a minol-piperidine-3-carboxylic The title compound is prepared in a manner analogous to that described in Example 134, using 1-cyanopropanecarboxylic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 524 [M + H] ": tR (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.54 minutes Example 153: Cyclopropyl-f4- (3 - (3-hydroxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p.41-oxazin-6-yl-amide of (3R, 5S) -5- ( 4-methyl-pentanoylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using 4-methyl-pentanoic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 529 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C1ß 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.87 minutes Example 154: Cyclopropyl-r4- (3-methoxy-propyl) -2.2-dimethyl-3-oxo-3,4-dihydro-2H- benzo- [(3R, 5S) -5-r (1-cyanopentanecarbonyl) -amino-1-piperidine-3-carboxylic acid benzo- [1,4-oxazin-6-yl-amide] The title compound is prepared in a manner analogous to that described in Example 134, using 1-cyanopentane-carboxylic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 552 [M + H] "; tR (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + acid 0.1 percent trifluoroacetic, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.60 minutes. Example 155: C idopropyl -T4- (3-methoxypropyl I) -2.2-di methyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-ill-amide (3R, 5S) -5- [2- (4- Hydroxy-tetrahydro-pi-ran-4-yl) -acetyl-amino-1-piperidin-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using (4-hydroxy-tetrahydro-pyran-4-yl) -acetic acid as the acid component, and EDCI and HOAt for the passage of acylation MS: 573 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C 8 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoric acid -acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.35 minutes The starting materials are prepared as follows: A. (4-Hydroxy-tetrahydro-pyran-4-yl) -acetic acid A a solution of ethyl acetate (2.3 milliliters, 24 millimoles) in tetrahydrofuran (60 milliliters), is added a 1M solution of lithium hexamethyl disilazide in tetrahydrofuran (24 milliliters, 24 mmol) at -78 ° C. After stirring for 1 hour at the same temperature, tetrahydro-4H-pyran-4-one (1.9 milliliters, 20 mmol) is added dropwise, and the reaction mixture is allowed to warm to room temperature for 2 hours. The reaction mixture is diluted with H20 and extracted with EtOAc. The combined organic phases are washed with H20 and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give a crude product. To a solution of (4-hydroxy-tetrahydro-pyran-4-yl) -acetic acid ethyl ester (1.85 grams) in 1,4-dioxane (5 milliliters) and H20 (5 milliliters), hydroxide is added. lithium (235 milligrams, 9.8 millimoles) at 0 ° C. After stirring for 7 hours at room temperature, the reaction mixture is diluted with H20 and extracted with Et20. The aqueous layer is acidified with 1N aqueous HCl and extracted with Et20. The combined organic phases are washed with H20 and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give a crude product. The material is used in the next step without purification. Example 156: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-in-amide acid ( 3R, 5S) -5- (4-hydroxy-4-methyl-pentanoylamino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using 4-hydroxy-4-methyl-pentanoic acid (Bioorganic &Medicinal Chemistry (2005), 13 (24), 6693-6702) as the acid component, and EDCI and HOAt for the acylation step. MS: 545 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.41 minutes Example 157: cyclopropyl-r4- (3-meth? Xi-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro- 2H-Benzo- [1,4-oxazin-6-ill-amide of (3R.5S) -5 - [(4-cyano-tetrah id ro-pi ran-4-carbon i I) -ami nol -piperidin -3-carboxylic The title compound is prepared in a manner analogous to that described in Example 134, using 4-cyano-tetrahydro-pyran-4-carboxylic acid (International Publication Number WO2005058860) as the acid component, and EDCI and HOAt for the acylation step. MS: 568 [M + H] ": tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, during 1 minute, flow: 0.5 milliliters / minute): 1.53 minutes. Example 158: C Cropropyl- [4- (3-methoxy-p-ro-pyl) -2,2-di-methyl-3-oxo-3,4-dihydro-2H-benzo-l, 41-oxazin-6 (3R, 5S) -5-f2-m and il-2- (tetrahydro-pi-ran-4-yl) -propionyl-aminol -pipe-ridin-3-carboxylic acid-amide The title compound is prepared in a manner analogous to that described in Example 134, using 2-methyl-2- (tetrahydro-pyran-4-yl) -propionic acid chloride (derived from the corresponding carboxylic acid, Publication International Number WO2005070870) for the acylation step. MS: 584 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C1ß 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.66 minutes Example 159: Ciclop ropil- [4- (3-methoxy-pro-pil) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-ill-amide (3R, 5S) -5- (2-tetrahydro-pi-ran-4-yl-propionyl-amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using 2- (tetrahydro-pyran-4-yl) -propionic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 571 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH Cie 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.56 minutes The starting materials are prepared as follows: A. 2- (Tetrahydro-pyran-4-yl) -propionic acid To a solution of the ethyl ester (tetrahydro-pyran-4-yl) -acetic acid (2.0 grams, 11.6 millimoles) in 50 milliliters of tetrahydrofuran at -78 ° C, dropwise add LDA (1.0 M, 17.4 milliliters, 34. 8 millimoles). The solution is stirred for 0.5 hours and treated with HMPA (3.2 milliliters, 9.3 millimoles) and Mel (4.94 grams, 34.8 millimoles). The reaction mixture is stirred at the same temperature for 0.5 hour and for 1.5 hours at 0 ° C, acidified with an aqueous solution of 1N HCl, and extracted twice with ether (40 milliliters, 2 times). The organic phase is washed with a saturated aqueous solution of NaCl, dried (MgSO 4), and concentrated in vacuo to give 1.8 grams of the ethyl ester of 2- (tetrahydro-pyran-4-yl) -propionic acid, the which is hydrolyzed without further purification. A solution of the crude ester (500 milligrams, 2.68 millimoles) and aqueous solution of 5N NaOH (2.68 milliliters, 13.4 millimoles) in dioxane-water (4 milliliters / 2 milliliters) is heated at 60 ° C for 2 hours. The solution is cooled to room temperature, acidified with an aqueous solution of 1N HCl, and extracted with ether. The ether layer is washed with a saturated aqueous solution of NaCl, dried over anhydrous MgSO, and concentrated in vacuo to give 400 milligrams of the title compound. MS: 159 [M + H] +; tR (HPLC, ACQUITY UPLCMR BEH C? 8 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.27 minutes. Example 160: f4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-H, 41-oxazin-6-yl-1-amide of (3R.5S) - 5-f (1-pyridin-4-yl-cyclopropane-carboniD-aminol -pipe ridin-3-carboxylic) The title compound is prepared in a manner analogous to that described in Example 134, using the component 1-pyridin-4-yl-cyclopropanecarboxylic acid, and EDCI and HOAt for the acylation step. MS: 576 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.24 minutes The starting materials are prepared as follows: A. 1-pyridin-4-yl-cyclopropane-carboxylic acid To a mixture of pyridin -4-yl-acetic acid (930 milligrams, 6.0 mmol) and 1-bromo-2-chloroethane (750 milligrams, 9.0 mmol) in an aqueous solution of 50 percent NaOH (5 milliliters), was added benzyl-triethyl-ammonium (680 milligrams, 3 mmol) The solution is heated to 60 ° C and stirred at that temperature for 2 hours. room temperature, the aqueous layer is removed, and the organic layer is neutralized with NH 4 Cl saturated aqueous, and extracted with Et20. The combined organic phases are washed with H20 and dried over Na2SO4. Concentration under reduced pressure gives the title compound. The material is used in a next step without purification. Example 161: r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-in-amide of (3R, 5S) - 5-α (1-pyridin-4-yl-cyclopropane-carboniD-aminol-pipe ridin-3-carboxylic) The title compound is prepared in a manner analogous to that described in Example 134, using the 4-pyridin-4-yl-tetrahydro-pyran-4-carboxylic acid component, and EDCI and HOAt for the acylation step. MS: 620 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.26 minutes The starting materials are prepared as follows: A. 4-pyridin-4-yl-tetrahydro-pyran-4-carboxylic acid To a mixture of pyridin-4-yl-acetic acid (930 milligrams, 6.0 mmol) and bis- (2-chloro-ethyl) -ether (1.1 milliliters, 9.0 mmol) in an aqueous 50% NaOH solution. milliliters), benzyl-triethylammonium chloride (680 milligrams, 3 millimoles) is added. The solution is heated to 60 ° C and stirred at that temperature for 2 hours. After cooling to room temperature, the aqueous layer is removed, and the organic layer is neutralized with saturated aqueous NH 4 Cl, and extracted with Et 20. The combined organic phases are washed with H20, and dried over Na2SO4. Concentration under reduced pressure gives the title compound. The material is used in a next step without purification. Example 162: C opropyl - [4- (3-m-ethoxy-p-ro-pyl) -2.2-di-methyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-yn -amino acid (3R, 5S) -5-y (1-pyridin-2-yl-cyclopentan-carbonyl) -aminol -pipe-ridin-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using 1-pyridin-2-yl-cyclopentanecarboxylic acid (International Publication Number WO 2002014277) as the acid component, and EDCI and HOAt for the acylation step. MS: 604 [M + H] "; tR (CombiScreen ODS-AM, 50 x 4.6 mm; 5 percent CH3CN + trifluoroacetic acid at 0.1 percent / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes , and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.23 minutes. Example 163: Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-p, 41-oxazin-6-ill-amide acid (3R, 5R) -5- (2-Oxo-2-y1 - (2H-tetrazol-5-yl) -cyclopropin-ethyl) -piperidine-3-carboxylic acid To a solution of the (3R.5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -5-. { [1 - (2H-tetraol-5-yl) -cyclopropane-carbonyl] -amino} -piperidin-1-carboxylic acid (89 milligrams, 0.107 millimoles) in tetrahydrofuran (10 milliliters), DBU (11 milligrams, 0.0107 millimoles) and N- (2-mercapto-ethyl) -amino-ethyl-polystyrene ( 2.1 millimoles / gram, 340 milligrams, 0.72 millimoles), and stirred for 1 hour at room temperature. The reaction mixture is filtered through a pad of Celite, and washed with tetrahydrofuran. Concentration in vacuo and purification by silica gel column chromatography give the title compound as a white solid. MS: 567 [M + H] "; tR (CombiScreen ODS-AM, 50 x 4.6 mm; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoroacetic acid at 0.1 percent, for 2 minutes, flow: 2.0 milliliters / minute): 2.27 minutes. The starting materials are prepared as follows: A. (3R.5S) -3- (cyclopropyl-r4- (3-methoxypropyl) -2H-9-fluoren-9-yl-methyl ester. dimethyl-3-oxo-3,4-dihydro-2H-benzo-f1, 41-oxazin-6-ill-carbamoyl) -5- (ri- (2H-tetraol-5-yl) -cyclopropane-carbonyl-1-amino) -pi pe ridi n-1 -carboxylic A microwave flask is charged with the (3S, 5R) -3 - [(1-cyano-cyclopropane-carbonyl) -amino acid 9H-fluoren-9-yl-methyl ester. ]-5-. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H- 'benzo- [1,4] -oxazin-6-yl] -carbamoyl} -piperidine-1-carboxylic acid (80 milligrams, 0.107 millimoles), azido-trimethyl-silane (0.06 milliliters, 0.645 millimoles), dibutyltin oxide (IV) (2.6 milligrams, 0.011 millimoles), and DME (2 milliliters). The reaction mixture is heated at 150 ° C for 20 minutes in a Discover CEM microwave reactor. After the mixture is cooled to room temperature, the mixture is concentrated under reduced pressure, to give the title compound as a yellow amorphous material, MS: 789 [M + H] "; tR (CombiScreen ODS-AM, 50 x 4.6 mm, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + acid 0.1 percent trifluoroacetic, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent of CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 3.90 minutes. B. (3S, 5R) -3 - [(1-cyano-cyclopropanecarbonyl) -aminol-5- (cyclopro? Il-r4- (3-methoxy) -9H-fluoren-9-yl-methyl ester propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4-oxazin-6-yl-carbamoyl) -piperidin-1-carboxylic acid To a solution of 9H- Fluoren-9-yl-methyl-ester of (3S, 5R) -3-amino-5- acid. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -piperidin-1 -carboxylic acid, hydrochloride salt (100 milligrams, 0.152 millimoles), and 1-cyano-cyclopropane-carboxylic acid (20 milligrams, 0.182 millimoles) in dimethylformamide (10 milliliters), EDC is added -HCI (45 milligrams, 0.227 millimoles), HOAt (31 milligrams, 0.227 millimoles), and di-isopropyl-ethyl-amine (0.04 milliliters, 0.227 millimoles) at 0 ° C. The mixture is stirred for 14 hours at room temperature, diluted with ethyl acetate, and washed with H20. The organic layer is dried over MgSO and evaporated in vacuo. The residue is purified by silica gel column chromatography to provide the title compound as a white solid. MS: 746 [M + H] +; tR (CombiScreen ODS-AM, 50 x 4.6 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.14 minutes.
Scheme 9 Example 164: C i clop ropil -f3-methoxy -5- (3-metox i -propoxy) -benzyl (3R *, 5S *) - 5-cyclohexyl-amino-piperidine-3-carboxylic acid amide A mixture of (3S *, 5R *) - 3-amino-5-terbutil-ester. { cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidin-1-carboxylic acid (42 milligrams, 0.085 millimoles), cyclohexanone (8.4 milligrams, 0.086 millimoles), and acetic acid (0.025 milliliters, 0.44 millimoles) in methanol, is stirred at room temperature for 1 hour. To the resulting mixture is added NaBH3CN (6 milligrams, 0.095 mmol), and the mixture is stirred for 3 hours. The mixture is purified by RP-HPLC, to give the desired amine, which is treated with 4N-1,4-dioxane HCl (1 milliliter) at room temperature for 1.5 hours. Concentration in vacuo gives the title compound as an amorphous white solid. MS: 473 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + acid trifluoroacetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.38 minutes. The starting material is prepared as follows: A. (3S *, 5R *) - 3-amino-5- (cyclopropyl-3-m-ethoxy-5- (3-methoxy-p-ropoxy) -be acid ester. ncill-carbamo i ll-pi pe ridi n-1 -carboxyl To a solution of cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy!) -benzyl] -amine (1.18 grams, 4.45 mmol) and triethylamine (0.68 milliliters, 4.90 millimoles) in tetrahydrofuran (20 milliliters) at room temperature, 2,4-dioxo-3-oxa-7-aza-bicyclo-tert-butyl ester [3.3.1] is added. ] -nonan-7-carboxylic acid (1.07 grams, 4.19 mmol) After stirring for 2 hours, the volume of the solvent is concentrated.The residue is diluted with EtOAc, and washed with aqueous KHS04, water, and brine, dried about Na2S04, filter, and concentrate. To a solution of a part of the residue (673 milligrams, 1.29 millimoles) in toluene (5 milliliters) at room temperature, add triethylamine (0.2 milliliters, 1.44 millimoles) and DPPA (0.31 milliliters, 1.43 millimoles). After stirring for 40 minutes, TMSCH2CH2OH (0.9 milliliters, 6.31 mmol) is added. The reaction mixture is refluxed for 2 hours. After dilution with EtOAc, the mixture is washed with aqueous KHS04, water, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to provide the desired carbamate (332 milligrams, 0.522 millimoles), which is treated with TBAF (410 milligrams, 1.57 millimoles) in tetrahydrofuran (5 milliliters) at 50 ° C. for 2.5 hours. After dilution with EtOAc, the mixture is washed with water (2 times) and brine, dried over Na 2 SO 4, filtered, and concentrated, to give the title compound as a pale yellow oil. MS: 491 [M + H] +; tR (HPLC, ACQUITY UPLCMR BEH C? 8 1.7 microns, 50 x 2.1 millimeters, 5 - 100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 2 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1 minute, flow: 0.5 milliliters / minute): 1.67 minutes. The amine used in Example 164A is prepared as follows: B. 3-Methoxy-5- (3-methoxy-propoxy) -benzoic acid methyl ester To a mixture of 3-methoxy-5-hydroxy-benzoic acid methyl ester (23.2 grams, 127 mmol), 3- toluene-4-sulfonic acid methoxy-propyl ester (40.7 grams, 167 millimoles), and Kl (2.23 grams, 13.4 millimoles) in dimethylformamide (350 milliliters), K2C03 (53.1 grams, 384 millimoles) is added under N2 After stirring at 60 ° C for 17 hours, the reaction mixture is supplemented with H20, and extracted with Et20. The combined organic phases are washed with H20 and dried (Na2SO4). Concentration under reduced pressure and flash chromatography on silica gel give the title compound as a colorless oil. MS: 255 [M + H] "; tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid , for 5 minutes, and then 100 percent CH3CN + trifluoroacetic acid at 0. 1 percent, for 2 minutes, flow: 2.0 milliliters / minute): 3.80 minutes. C. r3-methoxy-5- (3-methoxy-propoxy) -phenyl-methanol A mixture of 3-methoxy-5- (3-methoxy-propoxy) -benzoic acid methyl ester (5 grams, 19.7 mmol) and LAH (528 milligrams, 20 mmol) in tetrahydrofuran (110 milliliters), is stirred under N2 at 0 ° C for 3 hours. After adding H20, the reaction mixture is extracted with EtOAc. The combined organic phases are washed with H20, brine, and dried (Na2SO). Concentration under reduced pressure and flash chromatography on silica gel give the title compound as a colorless oil. MS: 227 [M + H] "'tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters, 5-100 percent d * e CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.85 minutes D. 3-methox? -5- (3 - me toxi-pro pox i) - benzaldehyde The title compound is synthesized by oxidation with Mn02 of [3-methoxy-5- (3-methoxy-propoxy) -phenyl] -methanol (4.20 grams, 18.6 millimoles) in toluene to ambient temperature for 12 hours Yellow oil MS: 225 [M + H] "'tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters, 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 3.59 minutes. E. Cyclopropyl-3-methoxy-5- (3-methoxy-propoxy) -benzyl-amine The title compound is synthesized by reductive amination of 3-methoxy-5- (3-methoxy-propoxy) -benzaldehyde (2.50 grams) , 11.1 mmol) with cyclopropyl-amine (855 milligrams, 15.0 mmol), in a manner analogous to the preparation of Example 152. Yellow oil; MS: 266 [M + H] "; tR (HPLC, CombiScreen ODS-AM 50 x 4.6 millimeters; 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid , for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 2 minutes, flow: 2.0 milliliters / minute): 2.48 minutes The cyclic anhydride used in Example 164A is prepared as follows: F. Dimethyl ester of pyridine-3,5-dicarboxylic acid Acid 3, 5-pyridine-dicarboxylic acid (1.5 grams, 63 mmol) and concentrated H2SO4 (0.9 milliliters) in methanol (15 milliliters), are heated in a microwave oven at 120 ° C for 2 hours. The solvent is evaporated, to give a residue, which is divided between ethyl acetate and saturated aqueous NaHCO 3. The organic phase is washed with brine, dried over Na 2 SO 4, filtered, and evaporated, to give a light yellow solid. MS (LC-MS): 196 [M + H] "TLC, Rf (ethyl acetate / hexane 1: 1) = 0.56.
G. Dimethyl ester of piperidine-3,5-dicarboxylic acid Dimethyl ester of pyridine-3,5-dicarboxylic acid (5.3 grams, 27 mmol) and Rh / Pt02 (0.5 g) in methanol (200 milliliters) are stirred under hydrogen overnight. The resulting mixture is filtered and the solvents are evaporated to leave a brown oil. MS (LC-MS): 202 [M + H] "H. 3.5-dimethyl ester of piperidin-1, 3,5-tricarboxylic acid 1-tert-butyl ester A solution of piperidine-3,5-dicarboxylic acid dimethyl ester (5.4 grams, 26.8 mmol) in CH2CI2 (55 milliliters), treated with Boc20 (6.4 grams, 29.5 mmol), and the reaction is stirred at room temperature overnight.The reaction is quenched with 0.1 N aqueous HCl and the organic phase is washed with water. 0.1 N aqueous HCl The combined aqueous phases are extracted twice with CH2Cl2 / MeOH (9/1) before the combined organic phases are dried over Na2SO4, filtered and evaporated, the resulting residue is purified by evaporation chromatography. Flash over silica gel (eluent: CH2Cl2 / MeOH, 95: 5) to give the title compound as a yellow solid MS (LC-MS): 302 [M + H] "TLC, Rf (CH2Cl2 / MeOH 95: 5) = 0.5. I. piperidin-1, 3,5-tricarboxylic acid 1-terbutyl ester To a solution of the piperidin-1,3-tricarboxylic acid 1-tert-butyl ester 3,5-dimethyl ester (6.8 grams, 22.5 millimoles) in MeOH / water (4: 1, 120 milliliters), K2C03 (9.4 grams, 68 millimoles) is added. The reaction is stirred at reflux overnight. He Methanol is evaporated and the residue is extracted with dichloromethane and 1N aqueous HCl. The organic phase is dried over Na 2 SO 4, filtered, and evaporated, to give a light yellow solid. MS (LC-MS): 274 [M + H] "J. Terbutilus-2,4-dioxo-3-oxa-7-aza-bicyclo-r3.3.nn-one-n -7-carboxylic acid ester A suspension of piperidin-1, 3,5-tricarboxylic acid 1-tert-butyl ester (1 gram, 3.6 mmol) in acetic anhydride (20 milliliters) is refluxed for 2 hours, the reaction mixture is evaporated 3 times with toluene before being dried under high vacuum at room temperature overnight to give a yellow solid MS (LC-MS): 278 [M + Na] ". Example 165: Ciclop ropil -f3-methoxy-5- (3-methoxy-propoxy) -benzyl (3R * .5S *) - 5-m-tolyl-amino-piperidine-3-carboxylic acid amide A mixture of (3S *, 5R *) - 3-amino-5- terbutil-ester. { cyclop ropil- [3-m-ethoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl I} -piperidin-1-carboxylic acid (40 milligrams, 0.081 millimoles), 3-bromo-toluene (16 milligrams, 0.094 millimoles), (rac) -2,2'-bis- (diphenyl-phosphino) -1, 1'-binaphthalene (3.8 milligrams, 0.006 millimoles), tris- (dibenzylidene-acetone) -dipaladium (O) (3.8 milligrams, 0.004 millimoles), and cesium carbonate (32 milligrams, 0.098 millimoles) in toluene (0.6 milliliters), is heated at 110 ° C for 36 hours. The mixture is purified by RP-HPLC to give the desired amine, which is treated with 4 N-1,4-dioxane HCl (1 milliliter) at room temperature for 1 hour. Concentration in vacuo gives the title compound as an amorphous white solid. MS: 481 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.07 minutes Example 166: C i clop ropil -T3- methoxy -5- (3-methoxy-propoxy) -benz and II-acid amide (3R *, 5S *) - 5- (6-chloro-pyrimidin-4-yl-amino) -piperidine-3-carboxylic acid To a solution of the terbutyl ester of (3S *, 5R *) - 3-amino-5- acid. { cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidin-1-carboxylic acid (50 milligrams, 0.10 millimole) in dimethyl- formamide (0.5 milliliters), it is added -Pr2NEt (26 microliters), 0.15 millimoles) and 4,6-dichloro-pyrimidine (23 milligrams, 0.15 millimoles). After stirring for 16 hours, the reaction mixture is quenched with H20 (30 milliliters) and extracted with EtOAc / Et20 (approximately 1: 1, 60 milliliters). The organic phase is washed successively with 5 percent aqueous KHS04, 5 percent aqueous NaHCO3, H20, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give the title compound protected by Boc. MS: 604 (CI35) [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.88 minutes. The compound protected by Boc is treated with 4N-1,4-HCl, to give the title compound as an amorphous white solid. MS: 504 (CI35) [M + H] "; tR (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoro- acid 0.1% acetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0. 5 milliliters / minute): 2.66 minutes. Example 167: Cyclopropyl-1 - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide acid (3R *, 5S *) - 5- (6-chloro-pyrimidin-4-yl- amino) -piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 154 using the (3S *, 5R *) - 3-amino-5-tert-butyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid and 4,6-dichloro-pyrimidine, followed by deprotection of Boc using TMSOTf and 2,6-lutidine. MS: 497 (CI35) [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoric acid -acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.77 minutes The starting material is prepared as follows: A. Terbutil-acid ester (3S *, 5R *) - 3-amino- 5- (cyclopropyl-f1 - (3- methoxy-propyl) -1 H -i ndol-3-yl-methyn-carbamoyl-piperidin-1-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 152A, using cyclopropyl- [1 - (3-methoxy-propyl) -1 H-indol-3-yl-methyl] -amine and 2,4-dioxo-3-oxa-7-aza-bicyclo- terbutilyl ester [3.3.1] -nonan-7-carboxylic acid. MS: 485 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C1ß 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, during 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 trifluoroacetic acid percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.09 minutes Example 168: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide acid (3R * , 5S *) - 5- (2-oxo-imidazolidin-1-yl) -piperidine-3-carboxylic acid The title compound is prepared by deprotection of the (3S *, 5R *) - 3- (2-amino-ethyl-amino) -5- (3S *, 5R *) -3- (3-amino-ethyl-amino) -terbutyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -carbamoyl} -piperidin-1-carboxylic acid, using TMSOTf and 2,6-lutidine. MS: 246 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, during 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 trifluoroacetic acid per cent, for 1.5 minutes, flow: 0.5 milliliters / minute): 4.54 minutes The starting materials are prepared as follows: A. Terbutil-acid ester (3S * .5R *) - 3- (2-amino-ethyl) -amino) -5- (cyclopropyl-H - (3-methoxy-propyl) -1 H -indol-3-yl-methyl-carbamoyl-piperidin-1 -carboxylic A mixture of the terbutil-ester of the acid (3R *, 5S *) - 3- { Cyclopropyl- [1 - (3-methoxy-propi I) -1 H -indol-3-yl-met i I] -carbamoi I.}. -5- [2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl-amino] -piperidine-1-carboxylic acid (160 milligrams, 0.24 mmol) and hydrocarbon monohydrate azine (18 microliters, 0.37 mmol) in EtOH, stirred at 60 ° C. After 6 hours, the reaction mixture is cooled to room temperature. The solution is filtered through a pad of Celite and the solvent is evaporated under vacuum to provide the title compound as a yellow material. MS: 528 [M + H] "; tR (HPLC, ACQUITY UPLC R BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 trifluoroacetic acid percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.93 minutes. B. (3R *, 5S *) - 3- (Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl-carbamoyl} -5-y2-tert-butyl ester. - (1,3-di-oxo-1,3-dihydro-isoindol-2-yl) -ethyl-aminol-pipe-ridin-1-carboxylic acid To a solution of the terbutil-ester of the acid (3R *, 5S *) - 3 - { Cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl.}. -5 - [[2- (1,3-dioxo-1,3) -dihyd ro-isoindol-2-yl) -ethyl] - (2-nitrobenzenesulfonyl) -amino] -piperidine-1-carboxylic acid (250 milligrams, 0.3 mmol) in dimethyl formamide (1 milliliter), add thioglycolic acid (104 microliters, 1.5 millimoles) and DBU (224 microliters, 1.5 millimoles) at room temperature After 2.5 hours, the reaction mixture is quenched with H20 (20 milliliters) and extracted with CH2CI2 (50 milliliters) The organic phase is washed successively with H20 and brine, then dried over Na2SO4 and concentrated under reduced pressure.The residue is purified by silica gel column chromatography to provide the compound. Title: MS: 658 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3. 60 minutes. C. (3R *, 5S *) - 3- (Cyclopropyl-H - (3-methoxy-propyl) -1H-indol-3-yl-methyl-carbamoyl) -5-rr2- (1R) ester , 3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl-1- (2-nitro-benzenesulfonyl) -aminol-piperidine-1-carboxylic acid To a solution of the terbutyl ester of the acid (3R *, 5S *) - 3-. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -5- (2-Nitro-benzenesulfonyl-amino) -piperidine-1-carboxylic acid (400 milligrams, 0.60 millimole), 2- (2-hydroxy-ethyl) -isoindole-1,3-dione (171 milligrams, 0.9 millimoles), and PPh3 (315 milligrams, 1.2 millimoles) in tetrahydrofuran, is added DEAD (208 milligrams, 1.2 millimoles) at room temperature, and then the mixture is stirred at 60 ° C. After 13 hours, the reaction mixture is quenched with H2O (20 milliliters) and extracted with EtOAc (50 milliliters). The organic phase is washed successively with 5 percent aqueous KHS0, H20, and brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide the title compound as an amorphous yellow material. MS: 843 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 4.41 minutes. D. Terbutil-acid ester (3R * .5S *) - 3-. { cyclopropyl-1 - (3-methoxy-propyl) -1H-indol-3-yl-methyl-carbamoyl) -5- (2-nitro-benzenesulfonyl-amino) -piperidine-1-carboxylic acid To a solution of the terbutil- (3S *, 5R *) - 3-amino-5-acid ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidin-1-carboxylic acid (400 milligrams, 0.83 millimoles) in CH2CI2 (1 milliliter), pyridine (1 milliliter) and o-nitro-benzenesulfonyl chloride (274 milligrams, 1.2 millimoles) are added at 0 ° C, and then the mixture is stirred at room temperature. After 20 hours, the reaction mixture is quenched with H20 (30 milliliters), and extracted with EtOAc (100 milliliters). The organic layer is washed successively with 5 percent aqueous KHS04, H20, and brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide the title compound as a brown amorphous material. MS: 670 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 4.14 minutes.
Scheme 10 Example 1 69: Cyclopropyl-f 1- (3R, 5S) -5- [benzyl- (2,2-dimethyl-propionyl) - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide-amide ) -amino-1-piperidine-3-carboxylic A solution of the (3S.5R) -3-benzyl-amino-5-9-fluoren-9-yl-methyl-ester ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol -3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (68.5 milligrams, 0.098 millimoles) in CH2CI2 is treated with / -Pr2NEt (40.2 microliters, 0.235 millimoles) and pivaloyl chloride (23.9 microliters, 0.196 millimoles). The solution is stirred at room temperature for 18 hours. Add / - Pr2NEt (20 microliters, 0.12 mmol) and additional pivaloyl chloride (12 microliters, 0.095 mmol), and stirring is continued for 9 hours. The reaction mixture is partitioned between EtOAc and 1M NaHCO 3, the organic layer is washed with 1M NaHCO 3, and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is dissolved in tetrahydrofuran / piperidine (5: 1) (6 milliliters), the solution is stirred at room temperature for 2.5 hours, and then concentrated in vacuo. The crude product is purified by RP-HPLC to provide the title compound. MS: 559 [M + H] ": tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.40 minutes.
Example 170: (3R, 5S) -5- (benzyl-cyclobutane-carbonyl-amino) -piperidin-3-cyclopropyl-H - (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide Icy carboxy The title compound is prepared in a manner analogous to that described in Example 134, using the (3S, 5R) -3-benzyl-amino-5-9-fluoren-9-yl-methyl-ester ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidin-1-carboxylic acid and cyclobutane-carbonyl chloride. MS: 557 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.34 minutes Example 171: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol-3-yl-methylamide of acid (3R, 5S) -5-r (2,2-dimethyl-propionyl) -isobutyl-amino-1-piperi di n -3-carboxylic The title compound is prepared in a manner analogous to that described in Example 134 using the (3R, 5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -5-isobutyl-amino-piperidine-1-carboxylic acid and pivaloyl chloride. MS: 525 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1% trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.29 minutes.
Example 172: Cyclopropyl-M - (3-methoxy-propyl) -1H-indol -3- and I-methyl-amide of (3R.5S) -5- (3-benzyl-1-isobutyl-ureido) -peridin-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134 using the (3R, 5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-m etyl] -carbamoyl I} -5-i sobut i I -am and no-piperidin-1 -carboxylic acid and benzyl isocyanate. MS: 574 [M + H] "'tR (HPLC, ACQUITY UPLCMR BEH C1ß 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.34 minutes. Example 173: Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl-amide of (3R.5S) -5-rcyclopropyl-methyl- (2,2-dimethyl-propionyl) -aminol-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134, using the (3R, 5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -i ndol-3-ylmethyl] -carbamoyl} -5- (cyclopropyl-methyl-amino) -piperidine-1-carboxylic acid and pivaloyl chloride. MS: 523 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H2O + 0.1 trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.24 minutes Example 174: ((3S, 5R) -5- (cyclopropyl-f1 - (3-methoxy-propyl)) terbutyl ester -1 H-indol-3-l-methyl-carbamoyl) -piperidin-3-yl) -cyclic opropylmethylcarbamic The title compound is prepared in a manner analogous to that described in Example 134 using the (3R, 5S) -3- acid 9H-fluoren-9-yl-methyl ester. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-m etyl] -carbamoyl} -5- (cyclopropyl-m ethi-amine) -pipe ridi n-1 -carboxylic acid and diterbutyl dicarbonate. MS: 539 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.46 minutes. The starting materials are prepared as follows: A. (3S.5R) -3-benzyl-amino-5-cyclopropyl-H - (3-methoxy-propyl) -9H-fluoren-9-yl-methyl ester 1 H-indol-3-yl-methyl-carbamoyl) -piperidin-1-carboxylic acid B. (3R, 5S) -3- (cyclopropyl-ri - (3- methoxy-propyl) -1 H -indol-3-yl-methyl-carbamoyl) -5-isobutyl-amino-piperidine-1-carboxylic acid C. 9H-fluoren-9-yl-methyl-ester (3R, 5S) -3- (cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl-1-carbamoyl) -5- (cyclopropyl-methyl-amino) -piperidine-1-carboxylic acid A solution of the 9H-Fluoren-9-yl-methyl-ester of (3S.5R) -3-amino-5- acid. { cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl} -piperidine-1-carboxylic acid (145 milligrams, 0.205 mmol) in CH2Cl2 is treated with the corresponding aldehyde (0.205 mmol), stirred at room temperature for 10 minutes, followed by the addition of NaBH (OAc) 3 (87 milligrams, 0.41 millimoles). The mixture is stirred for 88 hours, partitioned between EtOAc and 1M NaHCO 3. The organic layer is washed with 1M NaHC03, and brine, dried over MgSO4, filtered, and concentrated in vacuo. A. MS: 697 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 4.06 minutes B. MS: 663 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 0.5 minutes, then 5-100 percent of CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.98 minutes. C. MS: 661 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + acid trifluoro-acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.88 minutes.
Scheme 1 1 Example 175: Cyclopropyl-f4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-f-1,4-oxazin-6-yl-1-amide acid ( 3R.5S) -5-rmethyl- (1-phenyl-cyclopropane-carbonyl) -aminol-piperidine-3-carboxylic acid To a mixture of (3R, 5S) -3- tert-butyl ester. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -5-Methyl-amino-piperidin-1-carboxylic acid (110 milligrams, 0.2 mmol) and 1-f-1-cyclopropane-carboxylic acid (40 milligrams, 0.24 mmol) in dimethyl formamide (2 milliliters), add EDCI.HCI (60 milligrams, 0.3 millimoles) and HOAt (40 milligrams, 0.3 millimoles) at 0 ° C. After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc. The mixture is washed with water and dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (3R, 5S) -3- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3-tert-butyl ester. , 4-dih id ro-2H-benzo- [1,4] -oxazin-6-yl-carbamoyl] -5 - [(1-phenyl-cyclopropane-carbonyl) -amino] -piperidin-1-carboxylic acid as a material amorphous white, which is treated with 4N HCl in 1,4-dioxane (3 milliliters). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 589 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, then 100 percent CH3CN + trifluoroacetic acid 0.1% acetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.01 minutes.
The starting materials are prepared as follows: A. (3R.5S) -3- (cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-tert-butyl ester -dihydro-2H-benzo-ri, 41-oxazin-6-n-carbamoyl) -5-methyl-amino-piperidin-1-carboxylic acid To a solution of (3R, 5S) -3- (3R, 5S) -butyl ester. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -5- (2-nitro-benzenesulfonyl-amino) -piperidin-1-carboxylic acid (550 milligrams, 0.78 mmol) in dimethylformamide (5 milliliters), iodine-methane (81 microliters, 0.94 mmol) and K2C03 ( 320 milligrams, 2.3 millimoles) at room temperature. After stirring overnight, the reaction mixture is diluted with H20 and extracted with EtOAc. The combined organic phases are washed with H20 and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give the crude product. To a solution of the crude product in dimethyl formamide (3 milliliters), thioglycolic acid (160 microliters, 2.3 mmol) and LiOH (93 milligrams, 3.9 mmol) are added at room temperature. After stirring for 4 hours, the reaction mixture is diluted with H20 and extracted with EtOAc. The combined organic phases are washed with H20 and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give the title compound. MS: 545 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 trifluoroacetic acid one hundred, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.05 minutes. B. (3R, 5S) -3- (Cyclopropyl-r4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-ri, tert-butyl ester, 41- oxazin-6- jilea rbamoyl) -5- (2-nitro-benzenesulfonyl-amino) -piperidin-1-carboxylic acid To a solution of the hydrochloride of 9H-fluoren-9-yl-methyl-ester of the acid (3S, 5R) -3-amino-5-. { cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl} -piperidin-1-carboxylic acid (1.0 grams, 1.5 mmol) in CH2CI2 / H20 (5 milliliters / 5 milliliters), 2-nitro-benzenesulfonyl chloride (400 milligrams, 1.8 mmol), and sodium bicarbonate ( 480 milligrams, 4.5 millimoles) at 0 ° C. After stirring for 2 hours at this temperature, the reaction mixture is diluted with H20 and extracted with EtOAc. The combined organic phases are washed with H20 and dried over Na2SO4. Purification and concentration under reduced pressure, and filtration through silica gel, give the crude material. To the crude product (1.2 grams, 1.46 millimoles) in dimethylformamide (10 milliliters), KF (436 milligrams, 7.5 millimoles), Et3N (0.41 milliliters, 3.0 millimoles), and Boc20 (393 milligrams, 1.8 millimoles) were added at room temperature. . After stirring for 18 hours at room temperature, the reaction mixture is diluted with H20 and extracted with EtOAc. The phases The combined organic extracts are washed with H20 and dried over Na2SO4. Purification by column chromatography gives the title compound. MS: 716 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters; 5 percent CH3CN + trifluoroacetic acid 0.1 percent / H20 + trifluoroacetic acid 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + trifluoric acid -acetic at 0.1 percent, for 1.5 minutes, flow: 0.5 milliliters / minute): 3.94 minutes C. Hydrochloride of 9H-fluoren-9-yl-methyl-ester acid (3S.5R) -3-am i -5-f-cyclopropyl- [4- (3-toxy-propyl I) -2,2-di-methyl -3-oxo-3,4-dihydro-2H-benzo- [1,4-oxazin-6-] ill-carbamoyl) -pi pe ridi n-1 -carboxylic acid (3S, 5R) -3-terbutoxy-carbonyl-amino-5-. {cyclopropyl- [9H-fluoren-9-yl-methyl ester] 4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl.} - -piperidine- 1-carboxylic acid (3.0 grams, 4.0 mmol) is tr bind with 4N HCl in 1,4-dioxane (15 milliliters). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 653 [M + H] "; tR (HPLC, ACQUITY UPLCMR BEH C18 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid one hundred, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0. 5 milliliters / minute): 3.46 minutes. Example 176: C idopropyl -T4- (3-methoxypropyl I) -2,2-di methyl I -3-oxo-3,4-dihydro-2H-benzo-p, 4l-oxazin-6-ill-amide (3R, 5S) -5-Methyl- (2-tetrahydro-pyran-4-yl-acetyl) -aminol-piperidine-3-carboxylic acid The title compound is prepared in a manner analogous to that described in Example 134 (Iwasaki) using the (tetrahydro-pyran-4-yl) -acetic acid as the acid component, and EDCI and HOAt for the acylation step. MS: 571 [M + H] "; tR (HPLC, ACQUITY UPLC R BEH C? 8 1.7 microns, 50 x 2.1 millimeters, 5 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + trifluoroacetic acid at 0.1 percent, for 0.5 minutes, then 5-100 percent CH3CN + 0.1 percent trifluoroacetic acid / H20 + 0.1 percent trifluoroacetic acid, for 5 minutes, and then 100 percent CH3CN + 0.1 percent trifluoroacetic acid, for 1.5 minutes, flow: 0.5 milliliters / minute): 2.51min Example 177: Softgels 5,000 soft gelatin capsules are prepared, each comprising, as an active ingredient, 0.05 grams of either the compounds of formula I mentioned in any of the preceding Examples, as follows: Composition Active ingredient 250 grams Lauroglycol 2 liters Preparation process: The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefossé SA, Saint Priest, France) and milled in a wet pulverizer to produce a particle size of approximately 1 at 3 microns. Portions of 0.419 grams of the mixture are then filled into soft gelatin capsules using a capsule filling machine. Example 178: Tablets comprising the compounds of formula I Tablets comprising, as an active ingredient, 100 milligrams of any of the compounds of formula I in any of the preceding Examples, with the following composition, are prepared following conventional procedures: Composition Active ingredient 100 mg crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg magnesium stearate 5 mg 447 mg Manufacturing: The active ingredient is mixed with the carrier materials, and compressed by means of a tablet-forming machine (Korsch EKO, die diameter of 10 millimeters).
Avicel® is microcrystalline cellulose (FMC, Philadelphia, USA). PVPPXL is cross-linked polyvinyl-polypyrrolidone (BASF, Germany). Aerosil® is silicon dioxide (Degussa, Germany).

Claims (20)

1. A compound of the formula I: wherein: R1 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl; R2 is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; R3 is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted alkyl, R4 is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; or R3 and R4 can together form a 3 to 7 membered nitrogen ring containing a saturated hydrocarbon ring, which may be unsubstituted or substituted; Y
T is methylene or carbonyl; or a salt of it. 2. A compound of the formula I according to claim 1, wherein: R1 is hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; R2 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl; R3 is hydrogen or unsubstituted or substituted alkyl, R4 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl; or R3 and R4 can together form a 3 to 7 membered nitrogen ring containing a saturated hydrocarbon ring, which may be unsubstituted or substituted; and T is carbonyl (C (= 0)); or a salt (preferably pharmaceutically acceptable) thereof.
3. A compound of the formula I according to claim 1 or 2, wherein: R1 is hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; R2 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or cycloalkyl unsubstituted or substituted; R3 is hydrogen or unsubstituted or substituted alkyl, R4 is unsubstituted or substituted alkyl, or acyl; or R3 and R4 can together form a 3 to 7 membered nitrogen ring containing a saturated hydrocarbon ring, which may be unsubstituted or substituted; and T is carbonyl (C (= 0)); or a salt (preferably pharmaceutically acceptable) thereof.
4. A compound of formula I according to any of claims 1 to 3, wherein the general expressions have the following meanings: "Cy-Cy-" defines a fraction with up to and including maximum 7, especially up to and including maximum 4, carbon atoms, this fraction being branched chain (one or more times) or straight chain, and being linked by means of a terminal or non-terminal carbon atom; halo or halogen is fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine; unsubstituted or substituted alkyl is alkyl of 1 to 20 carbon atoms, more preferably alkyl of 1 to 7 carbon atoms, which is straight or branched chain one, or where appropriate, more times, which is unsubstituted or substituted by a or more, for example, up to three fractions selected from unsubstituted or substituted heterocyclyl as described below, in particular pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxetidinyl, 3- (alkyl of 1 to 7 carbon atoms) -oxetidinyl, pyridyl, pyrimidinyl, morpholino, thiomorpholino, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofurannonyl , tetrahydro-pyranyl, 1H-indazanyl, benzo-furanyl, benzo-thiophenyl, isoquinolinyl, quinolinyl or indolyl, each of which is unsubstituted or substituted as described below for unsubstituted or substituted heterocyclyl, for example, from one to three substituents independently selected from hydroxyl, halogen, such as chloro, alkyl of 1 to 7 carbon atoms, such as methyl, cyano and alkanoyl of 1 to 7 carbon atoms, such as acetyl; starting from unsubstituted or substituted cycloalkyl as described below, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or substituted as described below for unsubstituted or substituted cycloalkyl, especially for up to four fractions of alkyl of 1 to 7 carbon atoms; from unsubstituted or substituted aryl as described below, especially unsubstituted or substituted phenyl, naphthyl, indenyl or indanyl as described below; and from the group consisting of alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, as trifluoro-methoxy, hydroxy-alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenyl- or naphthyl-oxy, phenyl- or naphthy-alkyloxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, (alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-carbonyloxy, benzoyl- or naphthoyloxy, thioalkyl of 1 to 7 carbon atoms, halo-thioalkyl of 1 to 7 carbon atoms , such as trifluorothiomethyl, hydroxy-thioalkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-thioalkyl of 1 to 7 carbon atoms, thiophenyl or thionaphthyl, phenyl- or naphthylthioalkyl of 1 to 7. carbon, nitro, amino, mono- or di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, hydroxy atoms) -alkyl of 2 to 7 carbon atoms and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -amino, alkanoyl of 1 to 7 carbon atoms-amino, benzoyl- or na ftoyl-amino, alkyl of 1 to 7 carbon atoms-sulfonyl-amino, phenyl- or naphthyl-sulfonyl-amino, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfonyl-amino, phenyl- or naphthyl-alkyl from 1 to 7 carbon atoms-carbonyl-amino, carboxyl, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, phenyl- or naphthyloxycarbonyl, phenyl- or naphthyl-alkoxy 1 to 7 carbon atoms-carbonyl, carbamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-carbonyl, N-mono- or N, N-di- (naphthyl) - or phenyl-alkyl of 1 to 7 carbon atoms), hydroxy-alkyl of 2 to 7 carbon atoms and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -amino- carbonyl, cyano, sulfenyl (-S-OH), sulfonyl (-S (= 0) -OH), alkyl of 1 to 7 carbon atoms-sulfinyl (alkyl of 1 to 7 carbon atoms-S (= 0) - ), phenyl- or naphthyl sulfyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfinyl, sulfonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, phenyl- or naphthyl-sulfonyl, phenyl- or naphthyl -alkyl of 1 to 7 carbon atoms-sulfonyl, sulfamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, Naphthyl-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl and / or C 1-7 -alkoxy-C 1-7 -alkyl) -amino-sulfonyl, N-mono -, N'-mono-, N, N-di- or N, N, N'-tri- (alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-carbonyl-amino or -amino-carbonyloxy and N-mono-, N'-mono-, N, N-di- or N, N, N'-tri- (alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 2 to 7 carbon atoms, alkoxy 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl-amino; wherein any phenyl, naphthyl, indenyl, indanyl, pyridyl or indolinyl mentioned as a substituent or as part of a substituted alkyl substituent mentioned in the preceding paragraph is unsubstituted or substituted by one or more, preferably up to three, independently selected fractions from of the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy from 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, alkenyl of 1 to 7 carbon atoms, alkynyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, such as trifluoromethyl, halogen, especially fluorine, chlorine, bromine or iodine, (preferably, the following substituents -oxi are not bonded to the ring nitrogen) hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy from 1 to 7 carbon atoms, phenyloxyl, naphthyloxy, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkanoyloxy of 1 to 7 carbon atoms, amino , mono- or di- (alkyl of 1 to 7 carbon atoms), phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms and / or phenyl- or naphthyl-alkanoyl of one to 7 carbon atoms. carbon) -amino, carboxyl (preferably not bound to the ring nitrogen), alkoxy of 1 to 7 carbon atoms-carbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl-alkyloxy of 1 to 7 carbon atoms-carbonyl, C 1-7 carbonyl naphthyl alkoxy, carbamoyl, N-mono- or N, N-di- (C 1-7 -alkyl), phenyl, naphthyl, phenyl-C 1-7 -alkyl and / or naphthyl-alkyl of 1 to 7 carbon atoms) -aminocarbonyl, cyano, sulfonyl, sulfamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl and nitro, or preferably, where preferred substituents are mentioned, by one or more of these substituents mentioned; especially unsubstituted or substituted alkyl is phenyl-methyl, 2-cyclohexyl-2-phenyl-ethyl, 2,2-diphenyl-ethyl, 2,2-diphenyl-n-butyl, 2,3-diphenyl-n-propyl , naphthyl-methyl, 2-phenyl-2-pyridyl-ethyl, indolyl-methyl, 2-alkoxy, 1 to 7 carbon atoms-carbonyl-2,2-diphenyl-ethyl, 4-methyl-2-phenyl-n -pentyl or 5-alkoxy of 1 to 7 carbon atoms-2-diphenyl-methyl-pentyl, wherein any phenyl, naphthyl, pyridyl or indolyl mentioned as substituted alkyl substituent is unsubstituted or substituted by one or more, especially up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, ? -hydroxy-alkoxy of 2 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, halo-alkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 atoms d carbon, phenyl, halogen, especially chlorine or bromine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenoxy, halo-alkoxy of 1 to 7 carbon atoms, amino, alkanoyl of 1 to 7 carbon-amino atoms, alkane of 1 to 7 carbon atoms-sulfonyl and cyano; unsubstituted or substituted alkenyl is alkenyl of 2 to 20 carbon atoms, more preferably alkenyl of 2 to 7 carbon atoms with one or, if possible, more double bonds, which are straight or branched chain, which is unsubstituted or substituted by a or more, for example, up to three fractions selected from those mentioned as substituents for substituted alkyl and from unsubstituted or substituted aryl, each preferably as described above or below; unsubstituted or substituted alkynyl is alkynyl of 2 to 10 carbon atoms, more preferably alkynyl of 2 to 7 carbon atoms with one or, if possible, more triple bonds, which are straight or branched chain, which is unsubstituted or substituted by one or more, for example, up to three fractions selected from those mentioned as substituents for substituted alkyl and from unsubstituted or substituted aryl, each preferably as described above or below; unsubstituted or substituted aryl is a mono- or bicyclic aryl having 6 to 22 carbon atoms, especially phenyl, indenyl, indanyl or naphthyl, and is unsubstituted or substituted by one or more, especially one to three, fractions, preferably independently selected from the group consisting of: a substituent of the formula - (C 0 to C 7 alkylene) - (X) r- (C 1 to C 7 alkylene) - (Y) s- ( alkylene of 0 to 7 carbon atoms) -H wherein alkylene of 0 carbon atoms means that a bond is present instead of bound alkylene, alkylene in each case can be straight or branched chain, and is unsubstituted, or substituted by example, by one or more fractions as defined for substituted alkyl, especially by halogen, especially fluorine, hydroxyl, alkoxy of 1 to 7 carbon atoms, phenyloxy, naphthyloxy, alkanoyloxy of 1 to 7 carbon, benzoyloxy, naphthyloxy, amino, mono- or di- (alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenyl-alkanoyl of 1 to 7 carbon atoms, naphthyl-alkanoyl of 1 at 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl or cyano, rys, each independently of the other, are O or 1, and each of X and Y, if they are present and independently of the others, is -O-, -NV-, -S-, -O-CO- , -CO-O-, -NV-CO-; -CO-NV-; -NV-S02-, -S02-NV; -NV-CO-NV-, -NV-CO-O-, -O-CO-NV-, -NV-S02-NV-, wherein V is hydrogen or unsubstituted or substituted alkyl as defined above, especially alkyl from 1 to 7 carbon atoms, or is phenyl, naphthyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms or halo-alkyl of 1 to 7 carbon atoms; wherein the substituent of - (alkylene of 0 to 7 carbon atoms) - (X) - (alkylene of 1 to 7 carbon atoms) - (Y) s- (alkylene of 0 to 7 carbon atoms) -H it is preferably alkyl of 1 to 7 carbon atoms, such as methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl or tertiary butyl, haloalkyl of 1 to 7 carbon atoms, such as trifluoromethyl , hydroxy-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, such as 3-methoxy-propyl or 2-methoxy-ethyl,? -hydroxy-alkoxy 2 to 7 carbon atoms - alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms - alkoxy of 1 to 7 carbon atoms - alkyl of 1 to 7 carbon atoms carbon, phenyloxy- or naphthyloxy-alkyl of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, amino-alkyl of 1 to 7 carbon atoms, such as aminomethyl, alkoxy from 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms, mono- or di- (alkyl of 1 to 7 carbon atoms, naphthyl-, phenyl, naphthyl- alkyl of 1 to 7 carbon atoms and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-O-CO-NH-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-sulfonyl-amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-NH-CO-NH-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-NH-S02-NH-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, hydroxy-alkoxy 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, such as trifluoro-methoxy , phenyl- or naphthyl-alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-amino-carbonyloxy, halothioalkyl of 1 to 7 carbon atoms, such as trifluorothiomethyl, phenyl- or naphthylthioalkyl of 1 to 7 carbon atoms, mono- or di- (alkyl of 1 to 7 carbon atoms-, naphthyl-alkyl of 1 to 7 carbon atoms-, phenyl-alkyl of 1 to 7 carbon atoms) - and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-) amino, alkanoyl of 1 to 7 carbon atoms-amino, alkyl of 1 to 7 carbon atoms-sulfonyl-amino, phenyl- or naphthyl-alkanoyl of 1 to 7 carbon atoms-amino, phenyl- or naphthyl-alkyl of 1 to 7 carbon-amino-carbonyl-amino, carboxy-alkyl atoms of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-carbonyl, hydroxy-alkoxy of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon-alkoxy atoms of 1 to 7 carbon atoms-carbonyl, amino-alkoxy of 1 to 7 carbon atoms-carbonyl, (N-) mono- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 at 7 carbon atoms-carbonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkoxy of 1 to 7 carbon atoms-carbonyl, N- mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) , naphthyl-alkyl of 1 to 7 carbon atoms and / or phenyl-alkyl of 1 to 7 carbon atoms) -amino-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, halo-alkyl of 1 to 7 carbon atoms carbon-sulfonyl, hydroxy-alkyl of 1 at 7 carbon atoms-sulfonyl, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-sulfonyl, amino-alkyl of 1 to 7 carbon atoms-sulfonyl, N-mono- or di- (alkyl) from 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms-sulfonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms-sulfonyl, N-alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms-carbamoyl or N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-sulfonyl; from alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, phenyl, naphthyl, heterocyclyl, especially as defined below for heterocyclyl, preferably selected from pyrrolyl, furanyl, thienyl, pyrimidine-2,4-dione-1-, -3- or -5-yl and tetrahydro-furanyl, [phenyl- or naphthyl- or heterocyclyl or trihalo (especially trifluoro) -methoxy] -alkyl of 1 to 7 carbon atoms or -alkyloxy of 1 to 7 carbon atoms, wherein phenyl or naphthyl is preferably unsubstituted or substituted, preferably by alkoxy of 1 to 7 carbon atoms and / or halogen and wherein heterocyclyl is as defined below, preferably selected from pyrrolyl, furanyl, tetrahydro-furanyl, tetrahydro-pyranyl and thienyl; such as benzyl or naphthylmethyl, tetrahydro-furanyl- or tetrahydro-pyranyl-alkyl of 1 to 7 carbon atoms, benzoyl- or naphthoylamino-alkyl of 1 to 7 carbon atoms, (phenyl- or naphthyl- (especially mono- or bicyclic) heterocyclyl-) - sulfonyl-amino-alkyl of 1 to 7 carbon atoms, in where phenyl or naphthyl or heterocyclyl is unsubstituted or substituted, preferably by one or more, in particular one to three, alkyl fractions of 1 to 7 carbon atoms, (phenyl or naphthyl or (especially mono- or bicyclic) heterocyclyl) -alkyl of 1 to 7 carbon atoms-sulfonyl-amino-alkyl of 1 to 7 carbon atoms, halogen, hydroxyl, (heterocyclyl or phenyl or naphthyl) -oxyl, naphthyl-alkyloxy of 1 to 7 carbon atoms, benzoyl or naphthoyl or heterocyclyl-carbonyl) -oxyl, (phenyl or naphthyl or heterocyclyl) -amino-carbonyloxy, thio- (phenyl or naphthyl or heterocyclyl), thio- (benzoyl or naphthoyl or heterocyclyl), nitro, amino, di- ((naphthyl) or phenyl or heterocyclyl) -alkyl of 1 to 7 carbon atoms) -amino, (benzoyl or naphthoyl or heterocyclyl) -amino, (phenyl or naphthyl or heterocyclyl) -carbonyl of 1 to 7 carbon atoms-amino (phenyl or naphthyl or heterocyclyl) -sulfonyl-amino, wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially one to three fractions of alkyl of 1 to 7 carbon atoms, (phenyl or naphthyl or heterocyclyl) -alkyl of 1 to 7 carbon atoms-sulfonyl-amino, (phenyl or naphthyl or heterocyclyl) -amino-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) of 1 to 7 carbon atoms-amino-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) -oxy-carbonyl-amino, (phenyl or naphthyl or heterocyclyl) -alkyloxy from 1 to 7 carbon atoms-carbonyl-amino , carboxyl, alkyl of 1 to 7 carbon atoms-carbonyl, haloalkyl of 1 to 7 carbon atoms-carbonyl, hydroxy-alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-alkyl from 1 to 7 carbon atoms-carbonyl, amino-alkyl of 1 to 7 carbon atoms-carbonyl, (N-) mono- or (N, N-) di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms-carbonyl, alkanoyl of 1 to 7 carbon atoms-amino-alkyl of 1 to 7 carbon atoms-carbonyl, halo-alkoxy of 1 to 7 carbon atoms carbon-carbonyl, (phenyl or naphthyl or heterocyclyl (especially mono- or bi-cyclic)) - oxycarbonyl, (phenyl or naphthyl or (especially mono- or bicyclic) heterocyclyl) -alkoxyl of 1 to 7 carbon atoms -carbonyl, (N, N -) - di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms -carbonyl, carbamoyl, N-mono- or N, N-di- ( naphthyl or phenyl or (especially mono- or bicyclic) heterocyclyl) -amino-carbonyl, cyano, alkylene of 1 to 7 carbon atoms carbon that is unsubstituted or substituted by up to four alkyl substituents of 1 to 7 carbon atoms and bonded to two adjacent ring atoms of the aryl, sulfenyl, sulfinyl, C 1-7 -alkyl sulfinyl, (phenyl) moiety or naphthyl or (especially mono- or bicyclic) heterocyclyl) -sulfinyl, wherein phenyl or naphthyl is unsubstituted or preferably substituted by one or more, especially one to three, alkyl fractions of 1 to 7 carbon atoms, phenyl or naphthyl-alkyl of 1 to 7 carbon atoms-sulfinyl, sulfonyl, (phenyl or naphthyl or (especially mono- or bicyclic) heterocyclyl) -sulfonyl, wherein phenyl or naphthyl is unsubstituted or substituted by one or more , especially one to three, alkyl fractions of 1 to 7 carbon atoms, (phenyl or naphthyl or (especially mono- or bicyclic) heterocyclyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, sulfamoyl and N-mono - or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, (especially mono- or bicyclic) heterocyclyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms and / or heterocyclyl-alkyl of 1 to 7 carbon atoms) - amino-sulfonyl; wherein any phenyl or naphthyl or heterocyclyl (which heterocyclyl is preferably as defined for heterocyclyl, more preferably is selected from pyrrolyl, furanyl, tetrahydro-furanyl, tetrahydro-pyranyl and thienyl) mentioned as a substituent of, or as part of, a substituted aryl substituent (mentioned in one of the two preceding paragraphs, starting with a "substituent of the formula - (alkylene of 0 to 7 carbon atoms) carbon) - (X) r- (C 1-7 alkylene) - (Y) s- (C 7 -C 7 alkylene) -H ", and ending with" amino-sulfonyl "), is unsubstituted or substituted by one or more, preferably up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, alkenyl of 1 to 7 carbon atoms, alkynyl of 1 to 7 carbon atoms, halo -alkyl of 1 to 7 carbon atoms, such as trifluoromethyl, halogen, especially fluorine, chlorine, bromine or iodine, hydroxyl, alkoxy of 1 to 7 carbon atoms, phenyloxyl, naphthyloxy, phenyl- or naphthyl-alkoxy 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, phenyl- or naphthyl-alkanoyloxy of 1 to 7 carbon atoms, amino, mono- or di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl) from 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms and / or phenyl- or naphthyl-alkanoyl of 1 to 7 carbon atoms) -amino, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl, phenoxy -carbonyl, naphthyloxycarbonyl, phenyl-alkyloxy of 1 to 7 carbon atoms -carbonyl, naphthyl-alkoxy of 1 to 7 carbon atoms -carbonyl, carbamoyl, N-mono- or N, N-di- (alkyl of 1) at 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthylalkyl of 1 to 7 carbon atoms) -amino-carbonyl, cyano, sulfonyl, sulfamoyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino-sulfonyl and nitro, or preferably, where the substitutes are mentioned is preferred, by one or more of these mentioned substituents; unsubstituted or substituted heterocyclyl is a mono- or bicyclic heterocyclic moiety with an unsaturated, partially saturated, or saturated ring system, preferably 3 to 22, more preferably 3 to 14 ring atoms and with one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen and sulfur or which is unsubstituted or substituted by one or more, for example, up to three, substituents preferably independently selected from the substituents mentioned above for aryl, and from oxo and thioxo, preferably unsubstituted or substituted heterocyclyl is selected from the following fractions: * N ßr fV * H s xso ^ so. f s X C SO *? "SXO, CX X 'SO OR" SO * .- o O S S HN? NH HN? NH HN i? N.H H? PNIl? N i H HNN X,, N. NH HN A N.H XJ XJ and I p XX &x & kX? a ax axs ca-oí- o * O wherein, in each case, when an H linked to a ring atom is present by linking with the asterisk connecting the respective heterocyclyl moiety with the rest of the molecule, the H can be replaced with said link and, if they are present one or more additional H atoms bonded to a ring atom, may be replaced by one or more substituents as just described. Very preferred as unsubstituted or substituted heterocyclyl are tetrahydro-furanyl, tetrahydro-pyranyl, piperidinyl, pyridyl, thiophenyl, thiazolyl, pyrazolyl, indolyl, quinolinyl or 2H-1,4-benzoxazin-3 (4H) -onyl, each of which is unsubstituted or substituted by one or more, especially up to three substituents independently selected from the substituents mentioned for aryl previously substituted, especially by one or more, especially up to three, independently selected fractions from the group consisting of alkyl from 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenyl, halogen, especially chlorine or bromine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenoxy, halo- alkoxyl d and 1 to 7 carbon atoms, amino, alkanoyl of 1 to 7 carbon atoms-amino, alkane of 1 to 7 carbon atoms-sulfonyl, and cyano. unsubstituted or substituted cycloalkyl is preferably mono- or bi-cyclic, more preferably monocyclic, cycloalkyl of 3 to 10 carbon atoms, which may include one or more double and / or triple bonds, and is unsubstituted or substituted by one or more, eg, one to four substituents preferably independently selected from those mentioned above as substituents for aryl, especially cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted by up to four substituents selected from alkyl of 1 to 7 carbon atoms, from of phenyl (which is unsubstituted or substituted by one or more, especially up to three substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms - alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, oxo-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, phenyl, halogen, such as chlorine, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, halo-alkoxy of 1 to 7 carbon atoms, phenoxy, amino, alkanoyl of 1 to 7 carbon-amino atoms, carbamoyl, alkane of 1 to 7 carbon atoms-sulfonyl and cyano), from carbamoyl, and from cyano. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl which is unsubstituted or substituted by phenyl, halophenyl, carbamoyl and cyano are preferred; acyl is preferably unsubstituted or substituted aryl carbonyl, or -sulfonyl-, heterocyclyl-carbonyl or -sulfonyl-unsubstituted or substituted, unsubstituted or substituted cycloalkylcarbonyl, or -sulfonyl-, formyl or (unsubstituted or substituted alkyl, aryl-alkyl of 1 to 7 unsubstituted or substituted carbon atoms, unsubstituted or substituted heterocyclyl-alkyl of 1 to 7 carbon atoms or unsubstituted or substituted cycloalkyl-alkyl of 1 to 7 carbon atoms) -carbonyl or -sulfonyl, or (especially if it is bonded with N, S or O) unsubstituted or substituted alkyloxycarbonyl, unsubstituted aryl-oxycarbonyl or substituted, unsubstituted or substituted heterocyclyloxy-carbonyl, unsubstituted or substituted cycloalkyloxycarbonyl, aryloxy of 1 to 7 carbon atoms-unsubstituted or substituted carbonyl, heterocyclyloxy of 1 to 7 carbon atoms-unsubstituted or substituted carbonyl, cycloalkyloxy of 1 to 7 atoms carbon-unsubstituted or substituted carbonyl, or N-mono- or N, N-di- (unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, aryl-alkyl) from 1 to 7 carbon atoms unsubstituted or substituted, heterocyclyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, cycloalkyl-alkyl of 1 to 7 carbon atoms unsubstituted or substituted, or unsubstituted or substituted alkyl) -amino-carbonyl or -amino-sulfonyl, with the proviso that the oxy-carbonyl bond fractions are preferably bonded to a nitrogen atom in the remainder of the molecule; preferably the acyl fractions are alkanoyl of 1 to 7 carbon atoms which is unsubstituted or substituted by one or more, especially up to three, for example, one or two fractions independently selected from the group consisting of hydroxyl, amino, N- mono- or N, N-di-alkyl of 1 to 7 carbon atoms-amino and alkanoyl of 1 to 7 carbon atoms-amino, such as acetyl, 2-methyl-propionyl, 2-ethyl-butyryl, 3-methyl -butyryl, 3,3-dimethyl-butyryl, 2,2-di met i I -pro pió ni lo, 3, 3-dimet i I-bu ti rilo 3-h id rox i-2, 2 -di meti I -propy oni, N, N-dimethyl-amino-acetyl or 2- (N-acetylamino) -4-methyl-butyryl, benzoyl or unsubstituted naphthoyl, or mono-, di- or tri- (halo, alkoxy 1 to 7 carbon atoms and / or alkyl of 1 to 7 carbon atoms) -substituted, such as 4-methyl-benzoyl, or 3,4-dimethoxy-benzoyl, phenyl or naphthyl of 2 to 7 carbon atoms-alkanoyl wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially up to three, alkoxy substituents of 1 to 7 carbon atoms, such as 3-phenyl-propionyl, 2,2, -dimethyl-2-phenyl-acetyl or 3-ethoxy-phenyl-acetyl, cycloalkyl of 3 to 8 carbon atoms-carbonyl which is unsubstituted or substituted by one or more, for example, up to ro substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, carbamoyl and cyano, such as cyclopropyl-carbonyl, 2,2,3,3-tetramethyl-cyclopropyl-carbonyl, 1-carbamoyl-cyclopropyl- carbonyl, cyclobutylcarbonyl or 1-cyano-cyclopropylcarbonyl, benzo- [b] -thiophenylcarbonyl, such as benzo- [b] -thiophene-2-carbonyl, tetrahydro-furanylcarbonyl, such as tetrahydrofuran- 2-carbonyl, piperidinylcarbonyl which is unsubstituted or substituted by alkanoyl of 1 to 7 carbon atoms, such as 1-acetyl-piperidin-4-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, such as methyl-sulfonyl , (phenyl- or naphthyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, such as phenyl-methanesulfonyl, or ((phenyl- or naphthyl) -substituted sulphonyl or (mono-, di- or tri-) - substituted by [C 1-7 alkyl, phenyl, halo-lower alkyl, halogen, oxo-alkyl from 1 to 7 carbon atoms, alkyloxy of 1 to 7 carbon atoms, phenyl-alkoxy of 1 to 7 carbon atoms, haloalkyloxy of 1 to 7 carbon atoms, phenoxy, alkanoyl of 1 to 7 carbon atoms-amino, 1 to 7 carbon atoms-sulfonyl, cyano and / or alkyl of 1 to 7 carbon atoms-sulfonyl], wherein, if more than one substituent is present, the substituents are independently selected from those mentioned, such as methanesulfonyl, phenyl-methanesulfonyl, phenylsulfonyl (= benzenesulfonyl), naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, toluenes-4-sulfonyl, 4-isopropyl-benzenesulfonyl, biphenyl 4-sulfonyl, 2-trifluoro-m ethi I-benzenesulfonyl, 3-trif luoro-methyl-benzenesulfonyl, 4-trif-1-chloro-methyl-sulfonyl, 4-chloro-benzenesulfonyl, 3-chloro -benzene-sulfonyl, 2-chloro-benzenesulfonyl, 2,4-difluoro-benzenesulfonyl, 2,6-difluoro-benzenesulfonyl, 2,5-dichlorobenzenesulfonyl, 2,4-dichlorobenzene -sulfonyl, 3,4-dichloro-benzenesulfonyl, 3,5-dichloro-benzenesulfonyl, 2,3-dichloro-benzenesulfonyl, 3-methoxy-benzenesulfonyl, 4-methoxy-benzenesulphonyl, 2,5-dimethoxy-benzenesulfonyl, 2,4-dimethoxy-benzenesulfonyl, 4-trifluoro-methoxy-benzenesulfonyl, 2-benzyloxy-benzenesulfonyl, 4-f-enoxy-benzenesulfonyl, - (2-oxo-p-ro-pyl) -benzenesulfonyl, 3-acetyl-benzene-sulphonyl, 4-acetyl-amino-benzenesulfonyl, 4-cyan-o-benzenesulfonyl, 3-cyano-benzenesulfonyl, 2- cyan o-benzenesulf onyl or 4-methane-sulfonyl-benzenesulfonyl; halo-thiophene-2-sulfonyl, such as 5-chloro-thiophene-2-sulfonyl, quinolin-sulfonyl, such as quinolin-8-sulfonyl, thiazole-sulfonyl substituted by (C 1-7 -alkanoyl-amino and / or C 1-7 -alkyl), such as 2-acetylamino-4-methyl-thiazole-5 -sulfonyl, pyrazole-sulfonyl substituted by (halogen and / or alkyl of 1 to 7 carbon atoms), such as 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonyl, pyridine-sulfonyl, such as pyridine-3-sulfonyl, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms, (unsubstituted or substituted by alkyl of 1 to 7 carbon atoms and / or halogen) -phenyl or naphthyl, phenyl-C 1-7 -alkyl, naphthyl-C 1-7 -alkyl or C 3-8 -cycloalkyl) -amino-carbonyl, such as alkyl of 1 to 7 carbon atoms-amino-carbonyl , especially N-terbutyl-amino-carbonyl, N-phenyl-amino-carbonyl, N- (3-chloro-phenyl) -amino-carbonyl or phenyl-alkyl of 1 to 7 carbon-amino-carbonyl atoms, in particular N-benzyl-amino-carbonyl, or (alkyl of 1 to 7 carbon atoms, phenyl, naphthi it, phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms and / or alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms) -oxi-carbonyl, example, C 1 -C 7 alkoxycarbonyl, such as methoxyethylcarbonyl, isopropyloxycarbonyl, terbutyloxycarbonyl, isobutyloxycarbonyl, or 2- (methoxy) -ethoxycarbonyl, or phenyl-alkyloxycarbonyl; to 7 carbon atoms-carbonyl, such as benzyloxycarbonyl; and T is methylene (CH2) or preferably carbonyl (C (= 0)); or a salt (preferably pharmaceutically acceptable) thereof.
5. A compound of the formula I according to any of claims 1 to 4, wherein the fractions T-NR1R2 and NR3R4 are linked in the cis configuration with respect to the central piperidine, or a salt (preferably pharmaceutically acceptable) thereof .
6. A compound of the formula I according to any of claims 1 to 5, wherein the T-NR1R2 and NR3R4 fractions are linked in the trans configuration with respect to the central piperidine ring, or a salt (preferably pharmaceutically acceptable) ) of the same.
7. A compound of formula I according to claim 5, which has the configuration shown in the following formula IA: or a salt (preferably pharmaceutically acceptable salt) thereof, wherein R1, R2, T, R3 and R4 are as defined in any of the preceding claims for a compound of the formula I.
8. A compound of the formula I of according to claim 5, which has the configuration shown in the following formula IB: or a salt (preferably pharmaceutically acceptable salt) thereof, wherein R1, R2, T, R3 and R4 are as defined in any of the preceding claims for a compound of the formula I.
9. A compound of the formula I of according to claim 6, which has the configuration shown in the following IC formula: or a salt (preferably pharmaceutically acceptable salt) thereof, wherein R1, R2, T, R3 and R4 are as defined in any of the preceding claims for a compound of the formula I.
10. A compound of the formula I of according to claim 6, which has the configuration shown in the following formula ID: or a salt (preferably pharmaceutically acceptable salt) thereof, wherein R1, R2, T, R3 and R4 are as defined in any of the preceding claims for a compound of the formula I.
11. A compound of the formula I of according to any one of the preceding claims, wherein R 4 is selected from the group consisting of: acyl as shown in (a) to (o): (a) unsubstituted or substituted mono- or bi-cyclic arylcarbonyl, (b) unsubstituted or substituted mono- or bi-cyclic carbonyl, (c) unsubstituted or substituted mono- or bi-cyclic carbonyl cycloalkyl, (d) unsubstituted or substituted alkylcarbonyl, (e) aryl-1-alkyl; at 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl, (f) heterocyclyl-alkyl of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl, (g) cycloalkyl-1-alkyl; at 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl, (h) unsubstituted or substituted alkyloxycarbonyl, (i) mono- or bi-cyclic unsubstituted or substituted heterocyclyloxycarbonyl, (j) aryl-alkyloxy of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic carbonyl , (k) N-mono- or N, N-di- (unsubstituted or substituted mono- or bi-cyclic aryl, unsubstituted or substituted mono- or bi-cyclic cycloalkyl, aryl-alkyl of 1 to 7 carbon atoms, or unsubstituted or substituted bi-cyclic and / or unsubstituted or substituted alkyl) -aminocarbonyl, (I) unsubstituted or substituted mono- or bi-cyclic aryl sulfonyl, (m) unsubstituted mono- or bi-cyclic heterocyclylsulfonyl or substituted, (n) aryl-alkyl of 1 to 7 carbon atoms-unsubstituted or substituted mono- or bi-cyclic sulfonyl, (o) alkyl of 1 to 7 carbon atoms-unsubstituted or substituted sulfonyl, aryl-alkyl of 1 to 7 unsubstituted or substituted mono- or bi-cyclic carbon atoms, unsubstituted or substituted mono- or bi-cyclic cycloalkyl, mono-aryl or unsubstituted or substituted bi-cyclic, and unsubstituted or substituted mono- or bi-cyclic heterocyclyl.
12. A compound of the formula I according to any of claims 1 to 11, wherein: R 1 is hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl-alkyl of 1 to 7 atoms of carbon, R2 is phenyl-alkyl of 1 to 7 carbon atoms, naphthylalkyl of 1 to 7 carbon atoms, di- (phenyl) -alkyl of 1 to 7 carbon atoms, indenyl-alkyl of 1 to 7 carbon atoms , (phenyl-cycloalkyl of 3 to 8 carbon atoms) -alkyl of 1 to 7 carbon atoms, (phenyl) - (pyridyl) -alkyl of 1 to 7 carbon atoms, indolyl-alkyl of 1 to 7 carbon atoms , 4H-benzo- [1,4] -oxazin-3-on-yl, (alkoxy of 1 to 7 carbon atoms) -di- (phenyl) -alkyl of 1 to 7 carbon atoms or (alkoxy of 1 to 7 carbon-carbonyl atoms) -di- (phenyl) -alkyl of 1 to 7 carbon atoms, wherein each phenyl, naphthyl, pyridyl, indolyl or 4H-benzo- [1,4] -oxazin-3-on- ilo mentioned for R2 until now, is unsubstituted or substituted by one or more, in up to three, independently selected fractions from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, phenyl, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R3 is hydrogen, alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, especially up to three, fractions independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl and cyano; R 4 is phenyl-alkyl of 1 to 7 carbon atoms, wherein phenyl is unsubstituted or substituted by one or more, for example, up to three, independently selected fractions from the group consisting of halogen and alkoxy of 1 to 7 carbon atoms. carbon, in particular 2-, 3- or 4-chlorophenyl-methyl, alkanoyl of 1 to 7 carbon atoms which is unsubstituted or substituted by one or more, in particular up to three, for example, one or two independently selected fractions from the group consisting of hydroxyl, amino, N-mono- or N, N-di-alkyl of 1 to 7 carbon atoms-amino and alkanoyl of 1 to 7 carbon-amino atoms, especially acetyl, 2- methyl-propionyl, 2-ethyl-butyryl, 3-methyl-butyryl, 3,3-dimethyl-butyryl, 2,2-dimethyl-propionyl, 3,3-dimethyl-butyryl, 3-hydroxy-2,2-dimethyl -propionyl, N, N-dimethyl-amino-acetyl, 2- (N -acetyl-amino) -4-methyl-butyryl, benzoyl or unsubstituted naphthoyl or mono-, di- or tri-substituted by (halogen, alkoxy to 7 carbon atoms, and / or alkyl of 1 to 7 carbon atoms), especially 4-methyl-benzoyl or 3,4-dimethoxy-benzoyl, phenyl- or naphthyl-alkanoyl of 2 to 7 carbon atoms, wherein phenyl or naphthyl is unsubstituted or substituted by one or more, especially up to three, alkoxy substituents of 1 to 7 carbon atoms, especially 3-phenyl-propionyl, 2,2, -dimethyl-2-phenyl-acetyl or 3- ethoxy-phenyl-acetyl, cycloalkyl of 3 to 8 atoms carbon-carbonyl (= cycloalkancarbonyl) which is unsubstituted or substituted by one or more, for example, up to four substituents independently selected from the group consisting of alkyl of 1 to 7 carbon atoms, carbamoyl and cyano, especially cyclopropyl -carbonyl, 2,2,3,3-tetramethyl-cyclopropyl-carbonyl, 1-carbamoyl-cyclopropyl-carbonyl, cyclobutyl-carbonyl or 1-cyano-cyclopropyl-carbonyl, benzo- [b] -thiophenyl-carbonyl, especially benzo - [b] -thiophene-2-carbonyl, tetrahydro-furanyl-carbonyl, especially tetrahydro-furan-2-carbonyl, piperidinyl-carbonyl which is unsubstituted or substituted by alkanoyl of 1 to 7 carbon atoms, such as 1-acetyl -piperidine-4-carbonyl, alkyl of 1 to 7 carbon atoms-sulfonyl, such as methylsulfonyl, (phenyl- or naphthyl) -alkyl of 1 to 7 carbon atoms-sulfonyl, especially phenyl-methanesulfonyl, or (phenyl- or naphthyl) -sulfonyl (unsubstituted, or (mono-, di- or tri-) substituted by [alkyl of 1 to 7 carbon atoms] bond, phenyl, halo-lower alkyl, halogen, oxo-alkyl of 1 to 7 carbon atoms, alkyloxy of 1 to 7 carbon atoms, phenyl-alkoxy of 1 to 7 carbon atoms, halo-alkyloxy of 1 to 7 atoms carbon, phenoxy, alkanoyl of 1 to 7 carbon atoms-amino, alkyl of 1 to 7 carbon atoms-sulfonyl, cyano and / or alkyl of 1 to 7 carbon atoms-sulfonyl]), where, if present more than one substituent, the substituents are independently selected from those mentioned, especially methanesulfonyl, phenyl-methanesulfonyl, phenylsulfonyl, naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, toluenes-4-sulfonyl, 4-isopropyl-benzenesulfonyl, biphenyl-4-sulfonyl, 2-trifluoromethyl- benzenesulfonyl, 3-trifluoro-methyl-benzenesulfonyl, 4-t-rifluoro-met-1-sulfonyl, 4-chloro-benzenesulfonyl, 3-chloro-benzenesulfonyl, 2-chloro-benzenesulfonyl, 2,4-difluoro-benzenesulfonyl, 2,6-difluoro-benzenesulfonyl, 2,5-dichlorobenzenesulfonyl, 2,4-dichlorobenzenesulfonyl, 3,4-dichlorobenzenesulfonyl, 3,5-dichloro-benzenesulfonyl, 2,3-dichloro-benzenesulfonyl, 3-methoxy-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 2,5-dimethoxy-benzenesulfonyl, 2,4- dimethoxy-benzenesulfonyl, 4-t-rifluoromethoxy-benzenesulfonyl, 2-benzyloxy-benzenesulfonyl, 4-phenoxy-benzenesulfonyl, 4- (2-oxo-p-ropil) -benzenesulfonyl, 3 -acetyl-benzenesulfonyl, 4-acetyl-amino-benzenesulfonyl, 4-cyano-benzenesulfoyl, 3-cyano-benzenesulphonyl, 2-cyanobenzenesulphonyl or 4-methanesulphonylbenzene -sulfonyl; halo-thiophene-2-sulfonyl, in particular 5-chloro-thiophene-2-sulfonyl, quinolin-sulfonyl, especially quinolin-8-sulfonyl, thiazole-sulfonyl substituted by (alkanoyl of 1 to 7 carbon-amino atoms and / or alkyl of 1 to 7 carbon atoms), especially 2-acetylamino-4-methyl-thiazole-5-sulfonyl, pyrazole-sulfonyl substituted by (halogen and / or alkyl of 1 to 7 carbon atoms), in special 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonyl, pyridine sulfonyl, such as pyridine-3-sulfonyl, N-mono- or N, N-di- (alkyl of 1 to 7 atoms) carbon, phenyl or naphthyl (unsubstituted or substituted by alkyl of 1 to 7 carbon atoms and / or halogen), phenyl-alkyl of 1 to 7 carbon atoms, naphthyl-alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 at 8 carbon atoms) -aminocarbonyl, especially alkyl of 1 to 7 carbon atoms-amino-carbonyl, especially N-terbutyl-amino-carbonyl, N-phenyl-amino-carbonyl, N- (3- chloro-phenyl) -amino-carbonyl or phenyl-alkyl of 1 to 7 carbon atoms-amino-carbonyl, especially N-benzyl-amino-carbonyl, or (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl) -alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -oxi-carbonyl, for example, alkoxy of 1 to 7 carbon atoms-carbonyl, especially terbutyloxy-carbonyl or isobutyloxy- carbonyl, or phenyl-alkyloxy from 1 to 7 carbon atoms-carbonyl; and T is carbonyl; or a salt (preferably pharmaceutically acceptable) thereof.
13. A compound of the formula I, according to any one of claims 1 to 3, 4, 5, 6, 7, 8, 9 or 10, selected from the group of compounds with the following names: (2,2-diphenyl-ethyl) -amide (3S *, 5R *) - 5- (Toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, (3R *, 5R *) - (2,2-diphenyl-ethyl) -amide - (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide of (3S *, 5R *) - 5- (4-methoxy-benzenesulfonyl-amino) ) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- (5-chloro-thiophene-2-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide (3S *, 5R *) - 5- (quinoline-8-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, (2,2-diphenyl-ethyl) - (3S *, 5R *) - 5-phenyl-methanesulfonyl-amino-piperidine-3-carboxylic acid amide, (3S *, 5R *) - 5- (4-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, (2,2-diphenyl-ethyl) ) - (3S *, 5R *) - 5- (3-Chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid amide, (3S *) acid (2,2-diphenyl-ethyl) -amide , 5R *) - 5- (2-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide of (3S *, 5R *) - 5- (naphthalene 1-sulphonyl-amino) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- (4-methanesulfonyl-benzenesulfonyl-amino) (2,2-diphenyl-ethyl) -amide. -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- (4-trifluoro-methoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide, (3S *, 5R *) - 5- (4-isopropyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, (2,2-diphenyl-ethyl) ) - (3S *, 5R *) - 5-methansulfonyl-amino-piperidine-3-carboxylic acid amide, (3S *, 5R *) - (2S *, 5R *) - (2,2-diphenyl-ethyl) -amide - (2-acetylamino-4-methyl-thiazole-5-sulfonyl-amino) -piperidine-3-carboxylic acid, (2,2-d) (3S *, 5R *) - 5- (5-chloro-1,3-d-imethyl-1H-pyrazole-4-sulfonyl-amino) -piperidine-3-carboxylic acid (2S *, 5R *) - amide (2) , (3S *, 5R *) - 5- (2,4-difluoro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, 2-diphenyl-ethyl) -amide, (2,2-diphenyl-ethyl) -amide (3S *, 5R *) - 5- [4- (2-oxo-propyl) -benzenesulfonyl-amino] -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide acid (3S *, 5R *) - 5- (4-cyano- benzenesulfonyl-amino) -piperidine-3-carboxylic acid, (2S *, 5R *) - 5 - (2,6-di-fluoro-benzenesulfonyl-amino) (2,2-diphenyl-ethyl) -amide. ) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5 - (2-cyano-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide (3S *, 5R *) - 5 - (3-methoxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, (2,2-diphenyl-) (3S *, 5R *) - 5 - (2-trifluoro-methyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid ethyl), (2,2-diphenyl-ethyl) -amide of the acid ( 3S *, 5R *) - 5 - (4-acetyl ami no-be nce n-sulfon-il-amino) -pipe ridine n-3-carboxylic acid (2,2-diphenyl-ethyl) -amide ( 3S *, 5R *) - 5 - (pyridi n-3-sulfonyl-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide of (3S *, 5R *) - 5 - ( 3-Trifluoro-methyl-benzenesulfonyl-amino) -piperidine-3-carboxylic acid, (2S-5R *) - 5 (biphenyl-4-sulfonyl- (2,2-diphenyl-ethyl) -amide) amino) -piperidine-3-carboxylic acid (3S *, 5R *) - (2,2-diphenyl-ethyl) -amide - 5 (3-Cyano-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (3S *, 5R *) - 5 (3,4-dichlorobenzene) (2,2-diphenyl-ethyl) -amide -sulfonyl-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide of (3S *, 5R *) - 5 (2,5-di methoxy -be nce n -su Ifon il -amino) -pipe ridi n-3-carboxylic acid, (3S *, 5R *) - 5 - (4-phenoxy-benzenesulfonyl-amino) -piperidine- (2,2-diphenyl-ethyl) -amide. 3-carboxylic, (3S *, 5R *) - 5 (2,5-Dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl-ethyl) -amide, (2,2-diphenyl- (3S *, 5R *) - 5 (3,5-dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid ethyl), (2,2-diphenyl-ethyl) -amide of the acid ( 3S *, 5R *) - 5-benzenesulfonyl-amino-piperidine-3-carboxylic acid, (3S *, 5R *) - 5 - (2,4-dichloro- (2,2-diphenyl-ethyl) -amide) benzenesulfonyl-amino) -piperidine-3-carboxylic acid, (2S [5R]) - 5 - (naphthalene-2-sulfonyl-amino) -piperidin-3- (2,2-diphenyl-ethyl) -amide. carboxylic acid, (3S *, 5R *) - 5 - (2,3-dichloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid (2,2-diphenyl) -amide, (2,2- (3S *, 5R *) - 5 (2-benzyloxy-benzenesulfonyl-amino) -piperidine-3-carboxylic acid diphenylethyl-amide, (2,2-diphenyl-ethyl) -amide of the acid ( 3S *, 5R *) - 5 - (3-acetyl-benzenesulfonyl-amino) -piperidine-3-carboxylic, (3S *, 5R) -5- (naphthalene-1-yl-methyl) -amide. [bis- (3-chloro-benzyl) -amino] -piperidine-3-carboxylic, (2,2-diphenyl-ethyl) -ami (3S [5R *) - 5 (4-methyl-benzoyl-amino) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5 - (2,2-diphenyl-ethyl) -amide (2-Chloro-benzyl-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-ethyl) -amide of (3S *, 5R *) - 5 (3-chloro-benzyl-ami) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5 - [3- (3-chloro-) -3- (2-diphenyl-ethyl) -amide. phenyl) -ureido] -piperidine-3-carboxylic acid, (5S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine (5,6-diethyl-indan-2-yl) -amide. -3-carboxylic acid, (3R *, 5S *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (2-phenyl-2-pyridin-2-yl-ethyl) -amide, [3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid [1- (4-chloro-phenyl) -cyclopropyl-methyl] -amide, [2- (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (4-methoxy-phenyl) -2-phenyl-ethyl] -amide ,. { 2- [2- (4-methoxy-butoxy) -phenyl] -2-phenyl-ethyl} -amide of acid (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- ((biphenyl-2-ylmethyl) -amide) ( toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, [3- (4-methoxy-phenyl) -2-phenyl-propyl] -amide of (3S *, 5R **) - 5- (toluene- 4-sulfonyl-amino) -piperidine-3-carboxylic acid, (2S *, 5R *) - 5- (toluene-4) (2-phenyl-bicyclo- [3.3.1] -non-9-yl) -amide. -sulfonyl-amino) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidin-3 (2-chloro-benzyl) -cyclopropyl-amide -carboxylic acid, (3S *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid cyclopropyl- (2,2-diphenyl-ethyl) -amide, benzyl- ( (3S *, 5R *) - 5- (Toluene-4-sulfonyl-amino-piperidine-3-carboxylic acid, 3-methyl-2-phenyl-butyl) -amide, (2,2-diphenyl-ethyl) -amide of (3S, 5R) -5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, terbutil-acid ester. { (3R *, 5S *) - 5- [benzyl- (3-methyl-2-phenyl-butyl) -carbamoyl] -piperidin-3-yl} -carbamic, terbutil-acid ester ((3R *, 5S *) - 5 { cyclopropyl- [1 - (3-m-ethoxy-propyl I) -1H-indol-3-yl-methyl] -carbamoyl .} - -piperidin-3-yl) -carbamic acid, (3S *, 5R *) cyclopropyl- [1- (3-me toxi -propi I) -1H-indol-3-ylmethyl] -amide. -5- (3,3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid, ((3R *, 5S *) - 5-. {Cyclopropyl- [1 - (3-methoxy) -isobutyl) ester propyl) -1 H -indo I-3- i lm eti I] -carbamoi l.}. -pipe ridi n-3-i I) -carbamic, cyclopropyl- [1- (3-methoxy-propyl) -1 H 3- (3S *, 5R *) - 5- (2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic acid-3-ylmethyl] -amide ([3 (3-methoxy)] (3S *, 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid-1-propyl-3-ylmethyl] -amide, cyclopropyl- [1 (3S *, 5R *) - 5- (cyclobutyl-carbonyl-amino) -piperidine-3-carboxylic acid (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide, cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (3-benzyl-ureido) -piperidine- 3-carboxylic acid, cyclopropyl- [1 - (3-methoxypropyl I) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) -5- (3-cyclohexy) I-ureido) -pipe ridi n-3-carboxylic; cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -amide of (3S *, 5R *) - 5- (3-tert-butyl-ureido) -piperidine-3-carboxylic acid; (3S *, 5R *) - 5- [2- (3-methoxy-phenyl) -acetyl- cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide amino] -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S **, 5R *) - 5 - [(benzo- [b] -thiophen-2 -amide] -carbonyl) -amino] -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5-benzoyl-amino-piperidine-3-carboxylic acid; 3- (3S *, 5R *) - 5-acetylamino-piperidine-3-carboxylic acid cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (3,4-dimethoxy-benzoyl-amino) - piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amide of (3S *, 5R *) - 5- (3-phenyl-propionyl-amino) -piperidine- 3-carboxylic; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amide of (3S *, 5R *) - 5- (cyclohexane-carbonyl-amino) -piperidin-3 -amide carboxylic; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (3-methyl-butyryl-amino) -piperidine- 3-carboxylic; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (2-ethyl-butyryl-amino) -piperidine- 3-carboxylic; cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -amide of (3S *, 5R *) - 5 - [(2,2,3,3-tetramethyl-cyclopropane-carbonyl) -amin or] -pipe-ridin-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5 - [(tetrahydro-furan-2-carbonyl) -amino] ] -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amide of (3S *, 5R *) - 5-isobutyryl-amino-piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (cyclopropane-carbonyl-amino) -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amide of (3S *, 5R *) - 5- (2-methoxy-acetylamino) -piperidine- 3-carboxylic; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (2-methyl-2-phenyl-propionyl-amino) -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5 - ((S) -2-acetyl-amino-4 -amide methyl-pentanoylamino) -piperidine-3-carboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5- (2-dimethylamino-acetylamino) - piperidin-3-carboxylic acid; Cyclopropyl- [1 - (3-toxy-propi I) -1 H -indol -3-ylmethyl] -amide of (3S *, 5R *) - 5- (3-hydroxy-2,2) acid -dimethyl-propionyl-amino) -piperi di n -3-carboxylic acid; ((3R *, 5S *) - 5- { Cyclopropyl- [1- (3-methoxy-propyl) -1H-indole-3- il-methyl] -carbamoyl} -piperidin-3-yl) -amide amide of cyclopropan-1,1-dicarboxylic acid; Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3S *, 5R *) - 5 - [(1-cyano-cyclopropane-carbonyl) - amino] -piperidine-3-carboxylic acid; ((3R *, 5S *) - 5-. {cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-ylmethyl] -carbamoyl} -piperidine benzyl ester -3-il) -carbamic; ((3R *, 5S *) - 5-. {Cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-yl-methyl] -carbamoyl-2-methoxy-ethyl ester} -piperidin-3-yl) -carbamic acid; [4-Chloro-3- (3-methoxy-propoxy) -necyl] -cyclopropyl (3S *, 5R *) - 5- (2,2-dimethyl-p-pyrionyl-amino) -piperidine- 3-carboxylic; ((3R *, 5S *) - 5- { [4-chloro-3- (3-methoxy-p-ropoxy) -benzyl) -carboxylic acid ester -carbamoi I. -pi pe ridi n-3-i I) -carbámico; [4-Chloro-3- (3-m-ethoxy-propoxy) -benzyl] -cyclopropyl-amide of (3S *, 5R *) - 5- (cyclopropane-carbonyl-amino) -piperidine-3-carboxylic acid; 3S *, 5R *) - 5- (cyclobutane-carbonyl-amino) -piperidine-3-carboxylic acid [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropyl-amide; [3-Chloro-3-isobutyryl-amino-piperidine-3-carboxylic acid [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropy] -amide; 3- (3S *, 5R *) - 5- (3-tert-butyl-ureido) -piperidine-3-carboxylic acid [4-chloro-3- (3-methoxy-propoxy) -benzyl] -cyclopropi-amide; Cyclopropyl- [3- (3-methoxy-propoxy) -4-m-etyl-benzyl] -amide of (3S *, 5R *) - 5- (3-tert-butyl-ureido) -piperidine-3-carboxylic acid; cid opropi I- [3- (3-me toxy -propoxy) -4-m-etyl-benzyl] -amide of (3S *, 5R *) - 5- (3-benzyl-ureido) -piperidin-3 acid -carboxylic; ((3R *, 5S *) - 5-. {cyclopropyl- [3- (3-methoxy-p-ropoxy) -4-met i -benzyl] -carbamoyl} -piperidine- isobutyl ester 3-yl) -carbamic; Cyclopropi I - [3- (3-methoxy-propoxy) -4-methyl-I-benzyl] -amide of (3S *, 5R *) - 5- (2, 2-dimethyl-pro pionyl-amino) -piperidine -3-carboxylic acid; Cyclopropyl- [3- (3-methoxy-propoxy) -4-methyl-benzyl] -amide of (3S *, 5R *) - 5- (cyclobutane-carbonyl-amino) -piperidine-3-carboxylic acid; cid opropi I- [3-m-ethoxy-5- (3-methoxy-propoxy) -benzyl] -amide of (3S *, 5R *) - 5- (3-tert-butyl-ureido) -piperidin-3 -amide carboxyl; Cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -amide of (3S *, 5R *) - 5- (3-benzyl-ureido) -piperidine-3-carboxylic acid; ((3R *, 5S *) - 5-. {cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidin-3-yl) -isobutyl ester -carbamic; ((3R *, 5S *) - 5-. {cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -carbamoyl} -piperidin-3-yl) -butyl ester -carbamic; Cyclopropi I - [3- metoxy -5- (3-methoxy-propoxy) -benzyl] -amide of (3S *, 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidine -3-carboxylic acid; cyclopropi I - [3-m-ethoxy-5- (3-methoxy-propoxy) -benzyl] -am ida of (3S *, 5R *) - 5- (cyclobutane-carbonyl-amino) -piperidine-3-carboxylic acid; cid opropi I - [3-m-ethoxy-5- (3-methoxy-propoxy) -benzyl] -amide of (3S *, 5 R *) -5- (2, 2-di methi I -propi on il-amino) -pipe ridi n-3-carboxylic; (3S *, 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) -amide; 2-methoxy ethyl ester of the acid. { (3R *, 5S *) - 5- [cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl] -piperidin-3-yl} -carbamic; terbutil-acid ester. { (3R *, 5S *) - 5- [cyclopropyl- (2,3-dimethyl-benzyl) -carbamoyl] -piperidin-3-yl} -carbamic; (3S *, 5R *) - 5- (3,3-dimethyl-butyryl-amino) -piperidine-3-carboxylic acid cyclopropyl- (2,3-dimethyl-benzyl) -amide; 3-Cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide of (3R, 5S) -5- (2,2-dimethyl-propionyl-amino) - piperidine-3-carboxylic acid; (3R, 5S) -5- (3-tert-butyl-ureido) -piperidine-3-carboxylic acid cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-ylmethyl] -amide; Ethyl- [4- (3-methoxy-propyl) -3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3S *, 5R *) acid -5- (2,2-dimethyl-propionyl-amino) -piperidine-3-carboxylic acid; (3S *, 5R *) - 5- [methyl- (toluene-4-sulfonyl) -amino] -pipe-ridin-3-carboxylic acid (2,2-diphenyl) -amide, [2- (4 (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid-chloro-phenyl) -2-phenyl-ethyl] -amide, [3S *, 5R *) -5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (2,2-bis- (4-methoxy-phenyl) -ethyl] -amide, (2- (3S *, 5R *) - 5- (Toluene-4-sulfonyl-amino) -piperidine-3-carboxylic cyclohexyl-2-phenyl-ethyl) -amide, [2- (3-methoxy-methyl-phenyl) ) -2-phenyl-ethyl] -amide of acid (3S *, 5R *) - 5- (toluene-4-sulfo-n-amino) -piperidine-3-carboxylic acid, (2,2-diphenyl-butyl) -amide of (3S *, 5R *) - 5 - (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, (2- (4-chloro-phenyl) -3-methyl-butyl] -amide of (3S *, 5R *) - 5- (toluene) -4-sulfonyl-amino) -piperidine-3-carboxylic acid, ethyl ester of 2,2-diphenyl-3- acid. { [(3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carbonyl] -amino} -propionic acid (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid (4-methyl-2-phenyl-phenyl) -amide. { 2- [2- (3-methoxy-propoxy) -phenyl] -2-phenyl-ethyl} -amide of acid (3S *, 5R *) - 5- (Toluene-4-sulfo-nyl-amino) -piperidine-3-carboxylic acid, [2- (2-methoxy-phenyl) -2-phenyl-ethyl] -amide of the acid ( 3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, (5S *, 5R *) - (5-methoxy-2,2-diphenyl-pentyl) -amide 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid,. { 2- [2- (2-methoxy-ethoxy) -phenyl] -2-phenyl-ethyl} -amide of (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine-3-carboxylic acid, tert-butyl ester of the acid. { (3R *, 5S *) - 5- [cyclopropyl- (2,3-dioxide ro-benz I) -carbamoyl] -pipe ridine n-3- i} -carbamyl, (3S *, 5R *) - 5- (3-chloro-) acid (2,3-diphenyl-propyl) -amide benzenesulfonyl-amino) -piperidine-3-carboxylic acid, (3S *, 5R *) - 5- (toluene-4-sulfonyl-amino) -piperidine cyclopropyl- (2,3-dichloro-benzyl) -amide. -3-carboxylic acid, terbutil-ester. { (3R *, 5R *) - 5- [cyclopropyl- (2,3-dichloro-benzyl) -carbamoyl] -piperidin-3-yl} -carbamic acid, (3R *, 5R *) - 5- (3-chloro-benzenesulfonyl-amino) -piperidine-3-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) -amide, terbutyl ester ((3R *, 5R *) - 5-. {cyclopropyl- [1- (3-m-ethoxy-propyl) -1 H -indol-3-ylmethyl] -carbamoyl} -piperidin-3 -yl) -carbamic acid, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl ] - (3R, 5S) -5-phenyl-acetyl-amino-piperidine-3-carboxylic acid amide, cid opropi I- [4- (3-me toxi -propi I) -2, 2-di met i 1 -3-0X0-3,4-Dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- (2-Fe-noxy-acetyl) -amino ) -pipe ridi n-3-carboxylic, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] - Oxazin-6-yl] -amide of (3R, 5S) -5 - [(1-phenyl-cyclopropane-carbonyl) -amino] -piperidine-3-carboxylic acid, cyclop ropil- [4- (3- metoxi prop i I) -2, 2-di-methyl-l-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5 - (2-hydroxy-4-methyl-pentanoyl-amino) -piperidin- 3-carboxylic acid, cyclopropi I- [4- (3-metoximprop i I) -2, 2-di methi 1-3-0X0-3,4-dihydro-2H-benzo- [1,4] -oxazin -6-yl] -amido (3R, 5S) -5- (2-hydroxy-3-phenyl-propionyl-amino) -piperidine-3-carboxylic acid, ciclop ropil- [4- (3-toxy-propyl) -2,2-di met i l-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl ] - (3R, 5S) -5- (2-hydroxy-3-methyl-butyryl-amino) -piperidine-3-carboxylic acid amide, cid opropi I- [4- (3-me toxi -propi I) - 2, 2-di met i 1-3-0X0-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- [2- (tet rah id ro-p¡ran-4-loxi) -acetl-am i no] -p-pen-3-carboxylic acid, tetrahydro-pyran-4-yl-ester ((3S, 5R) -5- { Cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6 -yl] -carbamoyl.}. -piperidin-3-yl) -carbamic acid, cyclopropi I- [4- (3-methoxy-propi I) -2, 2-di methi 1-3-0X0-3,4-dihydro -2H-Benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- (2-hydroxy-methyl-3-methyl-butyryl-amino) -piperidine-3-carboxylic acid , ((3S, 5R) -5- { Cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzobutyl ester - [1,4] -oxazin-6-yl] -carbamoyl.} - -piperidin-3-yl) -carbamic acid, cyclopropyl- [4- (3-methoxy-pro phenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5-acetyl-amino -piperidine-3-carboxylic acid, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6 -yl] -amide of (3R, 5S) -5- [2- (piperid n -3- i I oxy) -acetyl-amy] - pipe ridi n-3-carboxylic acid, cyclopropi I - [4 - (3-methoxy-propi I) -2,2-di-methyl-l-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of the acid (3R) , 5S) -5- (2-tetrahydro-pyran-4-yl-acetylamino) -piperidine-3-carboxylic acid, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo -3,4- (3R, 5S) -5- (3-hydroxy-3-methyl-butyryl-amino) -piperidine-3-carboxylic acid dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of the acid ( 3R, 5S) -5 - [(tetrahydro-pyran-4-carbonyl) -amino] -piperidine-3-carboxylic acid, N - ((3S, 5R) -5- { Cyclopropyl- [4- (3-methoxy -propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -carbamoyl.} - piperidin-3-yl) -nicotinamide , cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of the acid (3R, 5S) -5-methanesulfonyl-amino-piperidine-3-carboxylic acid, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H 3- (3R, 5S) -5- (2,2-dimethyl-il-propionyl-amin) -piperidine-3-carboxylic acid-benzo- [1,4] -oxazin-6-yl] -amide, cyclopropyl - [4- (3-methoxy-propi I) -2,2-di methi 1-3-0X0-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide (3R, 5S) -5 - [(1-cyano-cyclop n-carbonyl) -am i no] -pipe ridi n-3-carboxy acid Icy, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide (3R, 5S) -5- (4-methyl-pentanoylamino) -piperidine-3-carboxylic acid, cyclopropi I- [4- (3-methoxy-propi I) -2, 2-di methi I -3- Oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5 - [(1-cyanopentane-carbonyl) -amino] - piperidine-3-carboxylic acid, cyclopropi I- [4- (3-methoxypropyl I) -2, 2-di methyl 1-3-0X0-3,4-dihydro-2H-benzo- [1,4] -oxazin -6-yl] -amide of (3R, 5S) -5- [2- (4- h id roxi -tet rah id ro-pi ran -4-il) -acetyl-am i no] -pipe ridi n-3-carboxylic, cyclop ropil- [4- (3-methoxy-propyl) -2,2 -dimet 1-3-0X0-3, 4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- (4-hydroxy-4-) acid methyl-pentanoylamino) -piperidine-3-carboxylic acid, cyclop ropil- [4- (3-toxy-propy I) -2, 2-di met i 1-3-0X0-3,4-dihydro-2H- benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5 - [(4-cyano-tet rah id ro-pi ran-4-ca rbonyl) -ami no] - pipe ridi n-3-carboxylic, cyclop ropil- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] - Oxazin-6-yl] -amide of (3R, 5S) -5- [2-methyl-2- (tetrahydro-pyran-4-yl) -propionyl-amino] -piperidine-3-carboxylic acid, cyclopropyl I- [4- (3-toxi-propy I) -2,2-dim eti-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide (3R, 5S) -5- (2-tetrahydro-pi-ran-4-yl-propionyl-amino) -piperidine-3-carboxylic acid, [4- (3-methoxy-propyl) -2,2- 3,4-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of the acid (3R), 5S) -5 - [(1-pyridin-4-yl-cyclopropane-carbonyl) -amino] -piperidine-3-carboxylic acid, [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo 3- (3R, 5S) -5 - [(1-pyridin-4-yl-cyclopropane-carbonyl) -3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide amino] -piperidine-3-carboxylic acid, cyclopropyl, I - [4- (3-methoxy-propyI) -2, 2-di methy1-3-0X0-3,4-dihydro-2H-benzo- [1, 4] -oxazin-6-yl] -amide of (3R, 5S) -5 - [(1-pyridin-2-yl-cyclopentan-ca-rbonyl) -amino] -piperidine-3-carboxylic acid, cyclopropyl- [4- (3-methoxy-propyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5R) -5-. { 2-oxo-2- [1 - (2 H -tet razol-5-I I) -cyclopropyl] -ethyl} -pipe ridi n-3-carboxyl, Cyclopropyl- [3-methoxy-5- (3-methoxy-propoxy) -benzyl] -amide of (3R *, 5S *) - 5-cyclohexyl-amino-piperidine-3-carboxylic acid, cyclopropyl I - [3-methoxy] -3- (3-methoxy-propoxy) -benzyl] -amide of (3R *, 5S *) - 5-m-tolyl-amino-piperidine-3-carboxylic acid, cyclopropyl- [3-methoxy-5-] (3R *, 5S *) - 5- (6-Chloro-pyrimidin-4-ylamino) -piperidine-3-carboxylic acid (3-methoxy-propoxy) -benzyl] -amide, cyclopropyl- [1- ( 3-methoxy-propyl) -1H-ndol -3-ylmethyl] -amide of the acid (3R *, 5S *) - 5- (6-chloro-pyrimidin-4-yl-amino) -piperidin-3 -carboxylic acid, cyclopropyl and I- [1- (3-toxi-propyl I) -1H-ndol -3-ylmethyl] -amide (3R *, 5S *) - 5- (2-oxo-) imidazolidin-1-yl) -pipe-ridi n-3-carboxylic acid, cyclopropi I - [1- (3-methoxy-propyI) -1 H -indol-3-ylmethyl] -amide of (3R, 5S) acid ) -5- [benzyl- (2,2 -dimethyl-propionyl) -amino] -piperi din-3-carboxylic acid, cyclop ropil- [1- (3-methoxy-propyl) -1 H-indol-3-yl -methyl] -amide (3 R, 5S) -5- (benzyl-cyclobutan-carbonyl-amino) -pipe-1-3-carboxylic acid, Cyclopropyl 1- (3R, 5S) -5 - [(2,2-dimethyl-propionyl) -isobutyl cyclopropyl 1- [3 - (3-methoxy-propyI) -1H-indol-3-ylmethyl] -amide] -amino] -piperidine-3-carboxylic acid, cyclopropyl- [1- (3-methoxy-propyl) -1H-indol-3-yl-methyl] -amide of (3R, 5S) -5- (3-benzyl) -amide 1-isobutyl-ureido) -piperidine-3-carboxylic acid, cyclopropyl, I - [1 - (3-methoxy-propyl) -1 H -indol-3-ylmethyl] -amide of the acid (3 R, 5S) -5- [cyclop ropil -met i I- (2, 2-di met i l-propi onil) -am i no] -pi pe ridi n -3 -carboxyl, terbutil- ((3S, 5R) -5-. {cyclopropyl- [1- (3-methoxy-propyl) -1 H -indol-3-ylmethyl] -carbamoyl} -piperidin-3-yl ester ) -cyclopropyl-methyl-carbamic acid, cyclopropyl l- [4- (3-methoxy-propyl) -2, 2-di-methyl-3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- [methyl- (1-phenyl-cyclopropane-carbonyl) -amino] -piperidine-3-carboxylic acid, and cyclopropyl- [4- (3- 3-oxo-3,4-dihydro-2H-benzo- [1,4] -oxazin-6-yl] -amide of (3R, 5S) -5- ([3-methoxy-propyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo- [ methyl- (2-tetrahyd ro-pi-ran-4-yl-acetyl) -amin o] -pipe ridin-3-car boxyl, or a salt (preferably pharmaceutically acceptable) thereof, respectively.
14. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 13, for use in the diagnosis or therapeutic treatment of a warm-blooded animal. A compound of the formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 13, for use according to claim 14, in the treatment of a disease which depends on the activity of the renin, especially hypertension. 16. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 15, for the manufacture of a pharmaceutical composition for the treatment of a disease that depends on the activity of renin, especially hypertension. 17. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 15, for the treatment of a disease that depends on the activity of renin, especially hypertension. 18. A pharmaceutical formulation, which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, as recited in any of claims 1 to 15, and at least one pharmaceutically acceptable carrier material. 19. A method of treating a disease that depends on the activity of renin, which comprises administering to a warm-blooded animal, especially a human being in need of such treatment, a pharmaceutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as mentioned in any of claims 1 to
15. 20. A process for the manufacture of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as given in any of claims 1 to 15, this process comprising: a) for the manufacture of a compound of the formula I, wherein R1 is hydrogen, and R2, R3, R4 and T are as defined for a compound of formula I in any of claims 1 to 9, reacting a compound of formula II: wherein R2, R3 and T are as defined for a compound of formula I, PX is R1 as defined for a compound of formula I, a protecting group or a linked resin, and PG is a protecting group, with a composed of formula III: R4-A (III) wherein R4 is as defined for a compound of formula I in any of claims 1 to 9, and A is activated hydroxyl; or b) reacting a compound of formula IV: wherein T is methylene or preferably carbonyl, PG is a protecting group, and R3 and R4 are as defined for a compound of the formula I in any of claims 1 to 9, or an activated derivative thereof, with a compound of the formula V: R1-NH-R2 (V) wherein R1 and R2 are as defined for a compound of the formula I in any of claims 1 to 9; or c) for the manufacture of a compound of formula I as given in claim 1, wherein R 1 is hydrogen, R 4 is N-mono- or N, N-di- (unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted alkyl) -aminocarbonyl, and R2, R3 and T are as defined for a compound of formula I in any of claims 1 to 9, reacting a compound of formula II as given in a) above, with a compound of formula VI: R4 * -NCO (VI) wherein R4 * is unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted alkyl; or d) for the manufacture of a compound of the formula I, wherein R 1 is hydrogen, R 4 is unsubstituted or substituted alkyl linked by means of a methylene group (which may be unsubstituted or substituted alkyl alkyl, or may be part of the same), and R2, R3 and T are as defined for a compound of the Formula I in any of claims 1 to 9, reacting a compound of formula II as given in a) above, with an oxo compound of formula VII: R4 ** - C (= 0) R4 * (Vil) wherein R4 ** and R4 *** with the bonding carbon atom are independently hydrogen or a fraction that completes an unsubstituted or substituted alkyl fraction R4 as given for a compound of claim 1 linked via the carbon bearing the oxo group (= 0) in the formula VII, under conditions of reductive amination; and, if desired, after any one or more of the processes mentioned above, converting a compound obtainable from formula I or a protected form thereof into a compound other than formula I, converting a salt of a compound which it can be obtained from the formula I in the free compound or in a different salt, converting a free compound that can be obtained from the formula I into a salt thereof, and / or separating a mixture of isomers obtainable from a compound of the formula I in the individual isomers; wherein, in any of the starting materials, in addition to the specific protective groups mentioned, there may be other protecting groups present, and any of the protective groups or linked resins are removed in one step suitable in order to obtain a corresponding compound of the formula I, or a salt thereof.
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